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Ying Z, Xin Y, Liu Z, Tan T, Huang Y, Ding Y, Hong X, Li Q, Li C, Guo J, Liu G, Meng Q, Zhou S, Li W, Yao Y, Xiang G, Li L, Wu Y, Liu Y, Mu M, Ruan Z, Liang W, Wang J, Wang Y, Liao B, Liu Y, Wang W, Lu G, Qin D, Pei D, Chan WY, Liu X. The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming. Nat Metab 2025; 7:940-951. [PMID: 40205158 DOI: 10.1038/s42255-025-01261-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 03/03/2025] [Indexed: 04/11/2025]
Abstract
The mitochondrial unfolded protein response (UPRmt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPRmt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPRmt activation at the early phase of pluripotency acquisition. UPRmt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPRmt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis3,4, our findings on the connection between the UPRmt and EMT have important pathological implications and reveal potential targets for tumour treatment.
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Affiliation(s)
- Zhongfu Ying
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China.
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
| | - Yanmin Xin
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Zihuang Liu
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Tianxin Tan
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yile Huang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Yingzhe Ding
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Xuejun Hong
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Qiuzhi Li
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Chong Li
- State Key Laboratory of Wheat Improvement, College of Life Sciences, Shandong Agricultural University, Tai'an, China
| | - Jingyi Guo
- Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Gaoshen Liu
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Qi Meng
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Shihe Zhou
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Wenxin Li
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yao Yao
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Ge Xiang
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Linpeng Li
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yi Wu
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yang Liu
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Miaohui Mu
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Zifeng Ruan
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Wenxi Liang
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Junwei Wang
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yaofeng Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Baojian Liao
- Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yang Liu
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Wuming Wang
- CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Gang Lu
- CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dajiang Qin
- Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Duanqing Pei
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China
| | - Wai-Yee Chan
- CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xingguo Liu
- GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China.
- Center for Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
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Peng B, Wang Y, Zhang H. Mitonuclear Communication in Stem Cell Function. Cell Prolif 2025; 58:e13796. [PMID: 39726221 PMCID: PMC12099226 DOI: 10.1111/cpr.13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024] Open
Abstract
Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.
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Affiliation(s)
- Baozhou Peng
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yaning Wang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Hongbo Zhang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
- The Department of Histology and Embryology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
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Amador-Martínez I, Aranda-Rivera AK, Martínez-Castañeda MR, Pedraza-Chaverri J. Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases. Mitochondrion 2025; 84:102040. [PMID: 40252890 DOI: 10.1016/j.mito.2025.102040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 04/05/2025] [Accepted: 04/16/2025] [Indexed: 04/21/2025]
Abstract
Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is a primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms to maintain mitochondrial quality control (MQC) and functions. In contrast, the perturbation of these mechanisms has been associated with the pathogenesis of several diseases. Thus, targeting specific pathways within MQC could offer a therapeutic avenue for protecting mitochondrial integrity. However, the mechanisms related to MQC and mitochondrial stress signaling in the cardio-renal axis have been poorly explored. The primary limitations include the lack of reproducibility in the experimental models of cardio-renal disease, the incomplete knowledge of molecules that generate bidirectional damage, and the temporality of the study models. Therefore, we believe that integration of all of those limitations, along with recent advances in MQC mechanisms (i.e., mitophagy), stress signaling pathways (e.g., integrated stress response, mitochondrial unfolded protein response, and mitochondrial protein import), associated pharmacology, and targeted therapeutic approaches could reveal what the deregulation of these mechanisms is like and provide ideas for generating strategies that seek to avoid the progression of cardio-renal diseases.
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Affiliation(s)
- Isabel Amador-Martínez
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio D, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, C.P. 04510, CDMX, Mexico; Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - Ana Karina Aranda-Rivera
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Mauricio Raziel Martínez-Castañeda
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; Programa de Doctorado en Ciencias Biomédicas, Unidad de Posgrado, Edificio B - 101, 1° Piso, Circuito de Posgrado, Ciudad Universitaria, Coyoacán, C.P. 04510, CDMX, Mexico
| | - José Pedraza-Chaverri
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico.
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Turkel I, Kubat GB, Fatsa T, Acet O, Ozerklig B, Yazgan B, Simsek G, Singh KK, Kosar SN. Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2025; 1866:149532. [PMID: 39675514 DOI: 10.1016/j.bbabio.2024.149532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/24/2024] [Accepted: 12/10/2024] [Indexed: 12/17/2024]
Abstract
Mitochondria are often referred to as the energy centers of the cell and are recognized as key players in signal transduction, sensing, and responding to internal and external stimuli. Under stress conditions, the mitochondrial unfolded protein response (UPRmt), a conserved mitochondrial quality control mechanism, is activated to maintain mitochondrial and cellular homeostasis. As a physiological stimulus, exercise-induced mitochondrial perturbations trigger UPRmt, coordinating mitochondria-to-nucleus communication and initiating a transcriptional program to restore mitochondrial function. The aim of this study was to evaluate the UPRmt signaling response to acute exercise in skeletal muscle. Male rats were subjected to acute treadmill exercise at 25 m/min for 60 min on a 0 % grade. Plantaris muscles were collected from both sedentary and exercise groups at various times: immediately (0), and at 1, 3, 6, 12, and 24 h post-exercise. Reactive oxygen species (ROS) production was assessed using hydrogen peroxide assay and dihydroethidium staining. Additionally, the mRNA and protein expression of UPRmt markers were measured using ELISA and real-time PCR. Mitochondrial activity was assessed using succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) staining. Our results demonstrated that acute exercise increased ROS production and upregulated UPRmt markers at both gene and protein levels. Moreover, skeletal muscle exhibited an increase in mitochondrial activity in response to exercise, as indicated by SDH and COX staining. These findings suggest that acute treadmill exercise is sufficient to induce ROS production, activate UPRmt signaling, and enhance mitochondrial activity in skeletal muscle, expanding our understanding of mitochondrial adaptations to exercise.
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Affiliation(s)
- Ibrahim Turkel
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey.
| | - Gokhan Burcin Kubat
- Department of Mitochondria and Cellular Research, Gulhane Health Sciences Institute, University of Health Sciences, Ankara, Turkey; Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey.
| | - Tugba Fatsa
- Gulhane Health Sciences Institute, University of Health Sciences, Ankara, Turkey
| | - Ozgu Acet
- Department of Pathology, Gulhane Training and Research Hospital, Ankara, Turkey
| | - Berkay Ozerklig
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Canada
| | - Burak Yazgan
- Department of Medical Services and Techniques, Sabuncuoglu Serefeddin Health Services Vocational School, Amasya University, Amasya, Turkey
| | - Gulcin Simsek
- Department of Pathology, Gulhane Training and Research Hospital, Ankara, Turkey
| | - Keshav K Singh
- Departments of Genetics, Dermatology and Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sukran Nazan Kosar
- Division of Exercise Nutrition and Metabolism, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
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Sanfrancesco VC, Hood DA. Acute contractile activity induces the activation of the mitochondrial integrated stress response and the transcription factor ATF4. J Appl Physiol (1985) 2025; 138:857-871. [PMID: 39417830 DOI: 10.1152/japplphysiol.00307.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 09/18/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
Skeletal muscle relies on mitochondria to produce energy and support its metabolic flexibility. The function of the mitochondrial pool is regulated by quality control (MQC) processes. The integrated stress response (ISR), a MQC pathway, is activated in response to various cellular stressors. The transcription factor ATF4, the main effector of the ISR, ameliorates cellular stress by upregulating protective genes, such as CHOP and ATF5. Recent literature has shown that the ISR is activated upon mitochondrial stress; however, whether this includes acute exercise-induced stress is poorly defined. To investigate this, a mouse in situ hindlimb protocol was utilized to acutely stimulate muscles at 0.25, 0.5, and 1 tetanic contraction/s for 9 min, followed by a 1-h recovery period. CAMKIIα and JNK2 were robustly activated sixfold immediately after the protocol. ISR activation, denoted as the ratio of phosphorylated to total eIF2α protein levels, was also elevated after recovery. Downstream, contractile activity induced an increase in the nuclear localization of ATF4. Robust twofold increases in the mRNA expression of ATF4 and CHOP were also observed after the recovery period. Changes in ATF4 mRNA were independent of transcriptional activation, as assessed with an ATF4 promoter-reporter plasmid. Instead, mRNA decay assays revealed an increase in ATF4 mRNA stability post contractile activity, as a result of enhanced stabilization by the RNA binding protein HuR. Thus, acute contractile activity is sufficient to induce mitochondrial stress and activate the ISR, corresponding to the induction of ATF4 with potential consequences for mitochondrial phenotype adaptations in response to repeated exercise.NEW & NOTEWORTHY The integrated stress response (ISR) is a mitohormetic stress response critical for the maintenance of mitochondrial homeostasis. However, its role in mediating mitochondrial adaptations with exercise-induced stress is not well established. This research demonstrates that acute contractile activity can elicit mitochondrial stress and activate the ISR to maintain mitochondrial homeostasis via the enhancement of the functioning of ATF4, illustrating an early response to exercise that promotes mitochondrial health and adaptations.
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Affiliation(s)
- Victoria C Sanfrancesco
- Muscle Health Research Centre, School of Kinesiology and Health ScienceYork University, Toronto, Ontario, Canada
| | - David A Hood
- Muscle Health Research Centre, School of Kinesiology and Health ScienceYork University, Toronto, Ontario, Canada
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6
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Wang F, Huynh PM, An YA. Mitochondrial Function and Dysfunction in White Adipocytes and Therapeutic Implications. Compr Physiol 2024; 14:5581-5640. [PMID: 39382163 DOI: 10.1002/cphy.c230009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up-to-date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581-5640, 2024.
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Affiliation(s)
- Fenfen Wang
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
| | - Phu M Huynh
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
| | - Yu A An
- Department of Anesthesiology, Critical Care, and Pain Medicine, Center for Perioperative Medicine, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
- Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
- Department of Biochemistry and Molecular Biology, McGovern Medical School, UT Health Science Center at Houston, Houston, Texas, USA
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7
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Li W, Dong M, Gao K, Guan J, Liu Y. Genome-wide CRISPR screens identify PTPN21 and WDR26 as modulators of the mitochondrial stress-induced ISR. LIFE METABOLISM 2024; 3:loae020. [PMID: 39872503 PMCID: PMC11749115 DOI: 10.1093/lifemeta/loae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/15/2024] [Accepted: 05/26/2024] [Indexed: 01/30/2025]
Affiliation(s)
- Wen Li
- State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Mingyue Dong
- State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Kaiyu Gao
- State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Jialiang Guan
- State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
- PKU-Tsinghua-NIBS Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Ying Liu
- State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics, Beijing 100871, China
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8
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Casas-Martinez JC, Samali A, McDonagh B. Redox regulation of UPR signalling and mitochondrial ER contact sites. Cell Mol Life Sci 2024; 81:250. [PMID: 38847861 PMCID: PMC11335286 DOI: 10.1007/s00018-024-05286-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/11/2024] [Accepted: 05/18/2024] [Indexed: 06/13/2024]
Abstract
Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.
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Affiliation(s)
- Jose C Casas-Martinez
- Discipline of Physiology, School of Medicine, University of Galway, Galway, Ireland
- Apoptosis Research Centre, University of Galway, Galway, Ireland
| | - Afshin Samali
- Apoptosis Research Centre, University of Galway, Galway, Ireland
- School of Biological and Chemical Sciences, University of Galway, Galway, Ireland
| | - Brian McDonagh
- Discipline of Physiology, School of Medicine, University of Galway, Galway, Ireland.
- Apoptosis Research Centre, University of Galway, Galway, Ireland.
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9
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Da W, Chen Q, Shen B. The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration. Biol Res 2024; 57:37. [PMID: 38824571 PMCID: PMC11143644 DOI: 10.1186/s40659-024-00494-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 04/03/2024] [Indexed: 06/03/2024] Open
Abstract
It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.
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Affiliation(s)
- Wacili Da
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Quan Chen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bin Shen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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10
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Sun Q, Bibi S, Xue Y, Du M, Chew B, Zhu MJ. Dietary purple potato supplement attenuates DSS-induced colitis in mice: impact on mitochondrial function. J Nutr Biochem 2024; 126:109585. [PMID: 38253109 DOI: 10.1016/j.jnutbio.2024.109585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 12/18/2023] [Accepted: 01/17/2024] [Indexed: 01/24/2024]
Abstract
Inflammatory bowel disease (IBD) is a condition characterized by disrupted intestinal barrier function, abnormal immune response, and mucosal structure loss. This study evaluated the beneficial role of purple potato (PP) supplementation against IBD symptoms using a murine model of dextran sulfate sodium (DSS)-induced colitis, and further explored the underlying mechanisms. Six-week-old C57BL/6J male mice were randomized into two groups and fed a standard rodent diet with or without 10% PP powder for 7 weeks. At the 5th week of dietary supplements, mice in each group were further divided into two subgroups and were either induced with or without 2.5% DSS induction for 7 days, followed by 7 days of recovery. Data showed that PP supplementation ameliorated the disease activity index in DSS-treated mice and reversed the colonic structure loss, mucosal damage, macrophage infiltration, and pro-inflammatory cytokine secretion induced by DSS in the colonic tissue. PP supplementation also restored the levels of tight junction proteins and caudal type homeobox 2 in DSS-treated mice. Furthermore, dietary PP enhanced peroxisome proliferator-activated receptor-γ coactivator-1α signaling pathway, mitochondrial biogenesis, mitochondrial proteostasis, and protein-folding capacity. In summary, dietary PP ameliorated DSS-induced colitis and improved gut structures and barrier function, which was associated with improved mitochondrial function. These results support further investigation of PP as a potential dietary intervention for IBD.
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Affiliation(s)
- Qi Sun
- School of Food Science, Washington State University, Pullman, WA, USA
| | - Shima Bibi
- School of Food Science, Washington State University, Pullman, WA, USA
| | - Yansong Xue
- School of Food Science, Washington State University, Pullman, WA, USA
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA, USA
| | - Boon Chew
- School of Food Science, Washington State University, Pullman, WA, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA, USA.
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11
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Dodge JD, Browder NJ, Pellegrino MW. Mitochondrial recovery by the UPR mt: Insights from C. elegans. Semin Cell Dev Biol 2024; 154:59-68. [PMID: 36792440 PMCID: PMC11684877 DOI: 10.1016/j.semcdb.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/15/2023]
Abstract
Mitochondria are multifaceted organelles, with such functions as the production of cellular energy to the regulation of cell death. However, mitochondria incur various sources of damage from the accumulation of reactive oxygen species and DNA mutations that can impact the protein folding environment and impair their function. Since mitochondrial dysfunction is often associated with reductions in organismal fitness and possibly disease, cells must have safeguards in place to protect mitochondrial function and promote recovery during times of stress. The mitochondrial unfolded protein response (UPRmt) is a transcriptional adaptation that promotes mitochondrial repair to aid in cell survival during stress. While the earlier discoveries into the regulation of the UPRmt stemmed from studies using mammalian cell culture, much of our understanding about this stress response has been bestowed to us by the model organism Caenorhabditis elegans. Indeed, the facile but powerful genetics of this relatively simple nematode has uncovered multiple regulators of the UPRmt, as well as several physiological roles of this stress response. In this review, we will summarize these major advancements originating from studies using C. elegans.
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Affiliation(s)
- Joshua D Dodge
- The University of Texas at Arlington, Department of Biology, Arlington, TX 76019, USA
| | - Nicholas J Browder
- The University of Texas at Arlington, Department of Biology, Arlington, TX 76019, USA
| | - Mark W Pellegrino
- The University of Texas at Arlington, Department of Biology, Arlington, TX 76019, USA.
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12
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Liu Z, Qiang Y, Shan S, Wang S, Liu Z, Yang Y, Huang Z, Song M, Zhao X, Song F. Aberrant mitochondrial aggregation of TDP-43 activated mitochondrial unfolded protein response and contributed to recovery of acetaminophen induced acute liver injury. Toxicol Res (Camb) 2024; 13:tfae008. [PMID: 38283824 PMCID: PMC10811519 DOI: 10.1093/toxres/tfae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 11/02/2023] [Accepted: 12/14/2023] [Indexed: 01/30/2024] Open
Abstract
Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.
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Affiliation(s)
- Zhaoxiong Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Yalong Qiang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Shulin Shan
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Shuai Wang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Zhidan Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Yiyu Yang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Zhengcheng Huang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Mingxue Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Xiulan Zhao
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
| | - Fuyong Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012, China
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13
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Diaba-Nuhoho P. Plant homeodomain-finger protein 5A: A key player in cancer progression. Biomed Pharmacother 2023; 169:115857. [PMID: 37951028 DOI: 10.1016/j.biopha.2023.115857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/31/2023] [Accepted: 11/05/2023] [Indexed: 11/13/2023] Open
Abstract
PHF5A is a member of the zinc-finger proteins. To advance knowledge on their role in carcinogenesis, data from experimental studies, animal models and clinical studies in different tumorigenesis have been reviewed. Furthermore, PHF5A as an oncogenic function, is frequently high expressed in tumor cells and a potential prognostic marker for different cancers. PHF5A is implicated in the regulation of cancer cell proliferation, invasion, migration and metastasis. Knockdown of PHF5A prevented the invasion and metastasis of tumor cells. Here, the role of PHF5A in different cancers and their possible mechanism in relation to recent literature is reviewed and discussed. There is an open promising perspective to their therapeutic management for different cancer types.
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Affiliation(s)
- Patrick Diaba-Nuhoho
- Department of Paediatric and Adolescent Medicine, Paediatric Haematology and Oncology, University Hospital Münster, Germany.
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14
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Cilleros-Holgado P, Gómez-Fernández D, Piñero-Pérez R, Romero-Domínguez JM, Reche-López D, López-Cabrera A, Álvarez-Córdoba M, Munuera-Cabeza M, Talaverón-Rey M, Suárez-Carrillo A, Romero-González A, Sánchez-Alcázar JA. Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases. Biomolecules 2023; 13:1789. [PMID: 38136659 PMCID: PMC10741690 DOI: 10.3390/biom13121789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Jose Antonio Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (P.C.-H.); (D.G.-F.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.); (M.Á.-C.); (M.M.-C.); (M.T.-R.); (A.S.-C.); (A.R.-G.)
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15
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Lee HC, Chao HT, Lee SYH, Lin CY, Tsai HJ. The Upstream 1350~1250 Nucleotide Sequences of the Human ENDOU-1 Gene Contain Critical Cis-Elements Responsible for Upregulating Its Transcription during ER Stress. Int J Mol Sci 2023; 24:17393. [PMID: 38139221 PMCID: PMC10744159 DOI: 10.3390/ijms242417393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
ENDOU-1 encodes an endoribonuclease that overcomes the inhibitory upstream open reading frame (uORF)-trap at 5'-untranslated region (UTR) of the CHOP transcript, allowing the downstream coding sequence of CHOP be translated during endoplasmic reticulum (ER) stress. However, transcriptional control of ENDOU-1 remains enigmatic. To address this, we cloned an upstream 2.1 kb (-2055~+77 bp) of human ENDOU-1 (pE2.1p) fused with reporter luciferase (luc) cDNA. The promoter strength driven by pE2.1p was significantly upregulated in both pE2.1p-transfected cells and pE2.1p-injected zebrafish embryos treated with stress inducers. Comparing the luc activities driven by pE2.1p and -1125~+77 (pE1.2p) segments, we revealed that cis-elements located at the -2055~-1125 segment might play a critical role in ENDOU-1 upregulation during ER stress. Since bioinformatics analysis predicted many cis-elements clustered at the -1850~-1250, we further deconstructed this segment to generate pE2.1p-based derivatives lacking -1850~-1750, -1749~-1650, -1649~-1486, -1485~-1350 or -1350~-1250 segments. Quantification of promoter activities driven by these five internal deletion plasmids suggested a repressor binding element within the -1649~-1486 and an activator binding element within the -1350~-1250. Since luc activities driven by the -1649~-1486 were not significantly different between normal and stress conditions, we herein propose that the stress-inducible activator bound at the -1350~-1250 segment makes a major contribution to the increased expression of human ENDOU-1 upon ER stresses.
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Affiliation(s)
- Hung-Chieh Lee
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan
| | - Hsuan-Te Chao
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan
| | - Selina Yi-Hsuan Lee
- Faculty of Sciences and Engineering, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Cheng-Yung Lin
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 25245, Taiwan
| | - Huai-Jen Tsai
- Department of Life Science, Fu-Jen Catholic University, New Taipei City 242062, Taiwan
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16
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Xu S, Liu H, Wang C, Deng Y, Xu B, Yang T, Liu W. Study of ATF4/CHOP axis-mediated mitochondrial unfolded protein response in neuronal apoptosis induced by methylmercury. Food Chem Toxicol 2023; 182:114190. [PMID: 37967789 DOI: 10.1016/j.fct.2023.114190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/18/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPRmt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPRmt. In this study, the role of the ATF4/CHOP axis-mediated UPRmt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPRmt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPRmt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPRmt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.
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Affiliation(s)
- Si Xu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Haihui Liu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Chen Wang
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Yu Deng
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Bin Xu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Tianyao Yang
- Department of Environmental Health, School of Public Health, China Medical University, China.
| | - Wei Liu
- Department of Environmental Health, School of Public Health, China Medical University, China.
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17
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Gressler AE, Leng H, Zinecker H, Simon AK. Proteostasis in T cell aging. Semin Immunol 2023; 70:101838. [PMID: 37708826 PMCID: PMC10804938 DOI: 10.1016/j.smim.2023.101838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/16/2023]
Abstract
Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.
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Affiliation(s)
- A Elisabeth Gressler
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany
| | - Houfu Leng
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, United Kingdom; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Heidi Zinecker
- Ascenion GmbH, Am Zirkus 1, Bertold-Brecht-Platz 3, 10117 Berlin, Germany
| | - Anna Katharina Simon
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany; Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, United Kingdom.
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18
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Khan SA, Reed L, Schoolcraft WB, Yuan Y, Krisher RL. Control of mitochondrial integrity influences oocyte quality during reproductive aging. Mol Hum Reprod 2023; 29:gaad028. [PMID: 37594790 DOI: 10.1093/molehr/gaad028] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 07/07/2023] [Indexed: 08/19/2023] Open
Abstract
Reduced quality in oocytes from women of advanced maternal age (AMA) is associated with dysfunctional mitochondria. The objective of this study was to investigate the mechanisms controlling mitochondrial quality during maternal aging in mouse and human oocytes. We first evaluated the expression of proteins involved in the mitochondrial unfolded protein response (UPRmt) and mitophagy in in vivo matured metaphase II (MII) oocytes collected from young and aged mice. Expression of UPRmt proteins, HSPD1 and LONP1, and mitophagy proteins, total-PRKN and phosphorylated-PRKN, was significantly decreased in aged compared to young oocytes. Treatment of aged oocytes during in vitro maturation with the mitochondrially targeted antioxidant mitoquinone (MQ) specifically restored total-PRKN and phosphorylated-PRKN expression to levels seen in young oocytes. We next investigated whether maturing young oocytes under a high-oxygen environment would mimic the effects observed in oocytes from aged females. Phosphorylated-PRKN expression in oxidatively stressed young oocytes was reduced compared to that in oocytes matured under normal oxygen levels, and the mitochondrial DNA (mtDNA) copy number was increased. Treating oxidatively challenged young oocytes with MQ restored the phosphorylated-PRKN expression and mtDNA copy numbers. Treatment of oxidatively challenged oocytes with MQ also increased the co-localization of mitochondria and lysosomes, suggesting increased mitophagy. These data correlated with the developmental potential of the oocytes, as blastocyst development and hatching of oxidatively stressed oocytes were reduced, while treatment with MQ resulted in a significant increase in blastocyst development and hatching, and in the percentage of inner cell mass. Consistent with our results in mice, MII oocytes from women of AMA exhibited a significant decrease in phosphorylated-PKRN and total-PRKN compared to those of young women. Our findings suggest that the protein machinery to control the health of the mitochondria via UPRmt and mitophagy may be compromised in oocytes from aged females, which may result in inefficient clearance of dysfunctional mitochondria and reduced oocyte quality.
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Affiliation(s)
- Shaihla A Khan
- Colorado Center for Reproductive Medicine, Lone Tree, CO, USA
- Genus plc, DeForest, WI, USA
| | - Laura Reed
- Colorado Center for Reproductive Medicine, Lone Tree, CO, USA
| | | | - Ye Yuan
- Colorado Center for Reproductive Medicine, Lone Tree, CO, USA
| | - Rebecca L Krisher
- Colorado Center for Reproductive Medicine, Lone Tree, CO, USA
- Genus plc, DeForest, WI, USA
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19
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Rath E. PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick. Front Cell Dev Biol 2023; 11:1270341. [PMID: 37705516 PMCID: PMC10495569 DOI: 10.3389/fcell.2023.1270341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 08/14/2023] [Indexed: 09/15/2023] Open
Affiliation(s)
- Eva Rath
- Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany
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20
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Wu D, Huang LF, Chen XC, Huang XR, Li HY, An N, Tang JX, Liu HF, Yang C. Research progress on endoplasmic reticulum homeostasis in kidney diseases. Cell Death Dis 2023; 14:473. [PMID: 37500613 PMCID: PMC10374544 DOI: 10.1038/s41419-023-05905-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023]
Abstract
The endoplasmic reticulum (ER) plays important roles in biosynthetic and metabolic processes, including protein and lipid synthesis, Ca2+ homeostasis regulation, and subcellular organelle crosstalk. Dysregulation of ER homeostasis can cause toxic protein accumulation, lipid accumulation, and Ca2+ homeostasis disturbance, leading to cell injury and even death. Accumulating evidence indicates that the dysregulation of ER homeostasis promotes the onset and progression of kidney diseases. However, maintaining ER homeostasis through unfolded protein response, ER-associated protein degradation, autophagy or ER-phagy, and crosstalk with other organelles may be potential therapeutic strategies for kidney disorders. In this review, we summarize the recent research progress on the relationship and molecular mechanisms of ER dysfunction in kidney pathologies. In addition, the endogenous protective strategies for ER homeostasis and their potential application for kidney diseases have been discussed.
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Affiliation(s)
- Dan Wu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Li-Feng Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Xiao-Cui Chen
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Xiao-Rong Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Hui-Yuan Li
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Ning An
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Ji-Xin Tang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China
| | - Hua-Feng Liu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China.
| | - Chen Yang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong, China.
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21
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Mitochondrial protein import and UPR mt in skeletal muscle remodeling and adaptation. Semin Cell Dev Biol 2023; 143:28-36. [PMID: 35063351 DOI: 10.1016/j.semcdb.2022.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 01/03/2023]
Abstract
The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPRmt). Protein import and UPRmt activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPRmt systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.
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22
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Kolac UK, Donmez Yalcin G, Karayel R, Yalcin A. The role of protein kinase R in placental inflammation, mtUPR and apoptosis. Placenta 2023; 139:200-211. [PMID: 37463546 DOI: 10.1016/j.placenta.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/20/2023]
Abstract
INTRODUCTION Placental inflammation is implicated in the pathophysiology of many pregnancy complications, including fetal growth restriction, preeclampsia, gestational diabetes, and choriocarcinoma. Mitochondrial dysfunction, one of the outcomes of placental inflammation, is characterized by loss of membrane potential, accumulation of oxygen radicals, mitochondrial protein folding defects, and disturbances in mitochondrial dynamics. Protein kinase R (PKR) is stimulated by double-stranded RNA and bacterial endotoxins in the presence of pathogens and is a critical immune response enzyme. PKR is also correlated with the cell death response during endoplasmic reticulum stress. In this study, we aim to investigate the effects of PKR activity stimulated by lipopolysaccharide (LPS), and double-stranded RNA analog (Poly I:C) on mitochondrial unfolded protein response (mtUPR), mitochondrial membrane potential, apoptosis, and oxidative stress in placental trophoblasts. METHODS We applied LPS and Poly I:C to BeWo cells to induce PKR activation. In addition, cells were treated with 2-aminopurine (2-AP) to inhibit the kinase activity of PKR. Protein levels of ATP-dependent Clp protease proteolytic subunit (CLPP) and heat shock protein 60 (HSP60) were determined after treatments. Apoptotic markers were detected by real-time PCR and flow cytometry. PKR-induced reactive oxygen radicals (ROS) accumulation and mitochondrial membrane potential change were assessed by flow cytometry. RESULTS It was determined that PKR activation-induced apoptosis in BeWo cells by reducing the levels of mtUPR proteins (CLPP and HSP60) and caused a decrease in mitochondrial membrane potential. PKR inhibition was sufficient for decreases in apoptotic markers and caused a reduction in the ratio of depolarized and ROS (+) cells. DISCUSSION Our results showed that LPS and Poly I:C administration stimulated PKR in BeWo cells in vitro. Furthermore, PKR activation is correlated with the levels of proteins involved in mitochondrial homeostasis and apoptosis. Our findings will contribute to understanding the role of PKR activation in placental inflammation and related diseases.
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Affiliation(s)
- Umut Kerem Kolac
- Department of Medical Biology, Faculty of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Gizem Donmez Yalcin
- Department of Medical Biology, Faculty of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Ramazan Karayel
- Department of Medical Biology, Faculty of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Abdullah Yalcin
- Department of Medical Biology, Faculty of Medicine, Aydin Adnan Menderes University, Aydin, Turkey.
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23
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Sutandy FXR, Gößner I, Tascher G, Münch C. A cytosolic surveillance mechanism activates the mitochondrial UPR. Nature 2023:10.1038/s41586-023-06142-0. [PMID: 37286597 DOI: 10.1038/s41586-023-06142-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 04/27/2023] [Indexed: 06/09/2023]
Abstract
The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
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Affiliation(s)
- F X Reymond Sutandy
- Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Ines Gößner
- Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Georg Tascher
- Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Christian Münch
- Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany.
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24
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Khalimonchuk O, Becker DF. Molecular Determinants of Mitochondrial Shape and Function and Their Role in Glaucoma. Antioxid Redox Signal 2023; 38:896-919. [PMID: 36301938 PMCID: PMC10171965 DOI: 10.1089/ars.2022.0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/07/2022] [Accepted: 10/22/2022] [Indexed: 01/12/2023]
Abstract
Significance: Cells depend on well-functioning mitochondria for essential processes such as energy production, redox signaling, coordination of metabolic pathways, and cofactor biosynthesis. Mitochondrial dysfunction, metabolic decline, and protein stress have been implicated in the etiology of multiple late-onset diseases, including various ataxias, diabetes, sarcopenia, neuromuscular disorders, and neurodegenerative diseases such as parkinsonism, amyotrophic lateral sclerosis, and glaucoma. Recent Advances: New evidence supports that increased energy metabolism protects neuron function during aging. Key energy metabolic enzymes, however, are susceptible to oxidative damage making it imperative that the mitochondrial proteome is protected. More than 40 different enzymes have been identified as important factors for guarding mitochondrial health and maintaining a dynamic pool of mitochondria. Critical Issues: Understanding shared mechanisms of age-related disorders of neurodegenerative diseases such as glaucoma, Alzheimer's disease, and Parkinson's disease is important for developing new therapies. Functional mitochondrial shape and dynamics rely on complex interactions between mitochondrial proteases and membrane proteins. Identifying the sequence of molecular events that lead to mitochondrial dysfunction and metabolic stress is a major challenge. Future Directions: A critical need exists for new strategies that reduce mitochondrial protein stress and promote mitochondrial dynamics in age-related neurological disorders. Discovering how mitochondria-associated degradation is related to proteostatic mechanisms in mitochondrial compartments may reveal new opportunities for therapeutic interventions. Also, little is known about how protein and membrane contacts in the inner and outer mitochondrial membrane are regulated, even though they are pivotal for mitochondrial architecture. Future work will need to delineate the molecular details of these processes.
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Affiliation(s)
- Oleh Khalimonchuk
- Department of Biochemistry, University of Nebraska–Lincoln, Lincoln, Nebraska, USA
- Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska–Lincoln, Lincoln, Nebraska, USA
- Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA
| | - Donald F. Becker
- Department of Biochemistry, University of Nebraska–Lincoln, Lincoln, Nebraska, USA
- Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska–Lincoln, Lincoln, Nebraska, USA
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25
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Wang Y, Li J, Zhang Z, Wang R, Bo H, Zhang Y. Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle. Life (Basel) 2023; 13:life13041006. [PMID: 37109535 PMCID: PMC10142204 DOI: 10.3390/life13041006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.
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Affiliation(s)
- Yan Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
- School of Physical Education, Guangdong Institute of Petrochemical Technology, Maoming 525000, China
| | - Jialin Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
| | - Ziyi Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
| | - Runzi Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
| | - Hai Bo
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
- Department of Military Training Medicines, Logistics University of Chinese People's Armed Police Force, Tianjin 300162, China
| | - Yong Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
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26
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Johns A, Higuchi-Sanabria R, Thorwald MA, Vilchez D. A tale of two pathways: Regulation of proteostasis by UPR mt and MDPs. Curr Opin Neurobiol 2023; 78:102673. [PMID: 36621224 PMCID: PMC9845188 DOI: 10.1016/j.conb.2022.102673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/28/2022] [Accepted: 12/08/2022] [Indexed: 01/07/2023]
Abstract
Mitochondrial fitness is critical to organismal health and its impairment is associated with aging and age-related diseases. As such, numerous quality control mechanisms exist to preserve mitochondrial stability, including the unfolded protein response of the mitochondria (UPRmt). The UPRmt is a conserved mechanism that drives the transcriptional activation of mitochondrial chaperones, proteases, autophagy (mitophagy), and metabolism to promote restoration of mitochondrial function under stress conditions. UPRmt has direct ramifications in aging, and its activation is often ascribed to improve health whereas its dysfunction tends to correlate with disease. This review pairs a description of the most recent findings within the field of UPRmt with a more poorly understood field: mitochondria-derived peptides (MDPs). Similar to UPRmt, MDPs are microproteins derived from the mitochondria that can impact organismal health and longevity. We then highlight a tantalizing interconnection between UPRmt and MDPs wherein both mechanisms may be efficiently coordinated to maintain organismal health.
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Affiliation(s)
- Angela Johns
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. https://twitter.com/AngyJohns
| | - Ryo Higuchi-Sanabria
- Leonard Davis School of Gerontology, University of Southern California. 3715 McClintock Ave, University Park Campus, Los Angeles, CA 90089, USA.
| | - Max A Thorwald
- Leonard Davis School of Gerontology, University of Southern California. 3715 McClintock Ave, University Park Campus, Los Angeles, CA 90089, USA.
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Institute for Genetics, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Faculty of Medicine, University Hospital Cologne, Cologne, Germany.
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27
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The Journey of Mitochondrial Protein Import and the Roadmap to Follow. Int J Mol Sci 2023; 24:ijms24032479. [PMID: 36768800 PMCID: PMC9916854 DOI: 10.3390/ijms24032479] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/19/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.
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28
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Ye Z, Chai R, Luan Y, Du Y, Xue W, Shi S, Wu H, Wei Y, Zhang L, Hu Y. Trends in mitochondrial unfolded protein response research from 2004 to 2022: A bibliometric analysis. Front Cell Dev Biol 2023; 11:1146963. [PMID: 37035249 PMCID: PMC10079909 DOI: 10.3389/fcell.2023.1146963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/17/2023] [Indexed: 04/11/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is a stress response pathway that regulates the expression of mitochondrial chaperones, proteases, and other proteins involved in protein folding and degradation, thereby ensuring proper mitochondrial function. In addition to this critical function, the UPRmt also plays a role in other cellular processes such as mitochondrial biogenesis, energy metabolism, and cellular signaling. Moreover, the UPRmt is strongly associated with various diseases. From 2004 to 2022, there has been a lot of interest in UPRmt. The present study aims to utilized bibliometric tools to assess the genesis, current areas of focus, and research trends pertaining to UPRmt, thereby highlighting avenues for future research. There were 442 papers discovered to be related to UPRmt, with the overall number of publications rising yearly. International Journal of Molecular Sciences was the most prominent journal in this field. 2421 authors from 1,402 institutions in 184 nations published studies on UPRmt. The United States was the most productive country (197 documents). The top three authors were Johan Auwerx, Cole M Haynes, and Dongryeol Ryu. The early focus of UPRmt is "protein." And then the UPRmt research shifted from Caenorhabditis elegans back to mammals, and its close link to aging and various diseases. The top emerging research hotspots are neurodegenerative diseases and metabolic diseases. These findings provide the trends and frontiers in the field of UPRmt, and valuable information for clinicians and scientists to identify new perspectives with potential collaborators and cooperative countries.
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Affiliation(s)
| | | | | | | | | | | | | | - Yi Wei
- *Correspondence: Yi Wei, ; Limei Zhang, ; Yuanhui Hu,
| | - Limei Zhang
- *Correspondence: Yi Wei, ; Limei Zhang, ; Yuanhui Hu,
| | - Yuanhui Hu
- *Correspondence: Yi Wei, ; Limei Zhang, ; Yuanhui Hu,
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29
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Tjahjono E, Kirienko DR, Kirienko NV. The emergent role of mitochondrial surveillance in cellular health. Aging Cell 2022; 21:e13710. [PMID: 36088658 PMCID: PMC9649602 DOI: 10.1111/acel.13710] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 08/12/2022] [Accepted: 08/29/2022] [Indexed: 01/25/2023] Open
Abstract
Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.
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30
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Zhou Z, Fan Y, Zong R, Tan K. The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases. Ageing Res Rev 2022; 81:101702. [PMID: 35908669 DOI: 10.1016/j.arr.2022.101702] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 02/06/2023]
Abstract
Mitochondria, which serve as the energy factories of cells, are involved in cell differentiation, calcium homeostasis, amino acid and fatty acid metabolism and apoptosis. In response to environmental stresses, mitochondrial homeostasis is regulated at both the organelle and molecular levels to effectively maintain the number and function of mitochondria. The mitochondrial unfolded protein response (UPRmt) is an adaptive intracellular stress mechanism that responds to stress signals by promoting the transcription of genes encoding mitochondrial chaperones and proteases. The mechanism of the UPRmt in Caenorhabditis elegans (C. elegans) has been clarified over time, and the main regulatory factors include ATFS-1, UBL-5 and DVE-1. In mammals, the activation of the UPRmt involves eIF2α phosphorylation and the uORF-regulated expression of CHOP, ATF4 and ATF5. Several additional factors, such as SIRT3 and HSF1, are also involved in regulating the UPRmt. A deep and comprehensive exploration of the UPRmt can provide new directions and strategies for the treatment of human diseases, including aging, neurodegenerative diseases, cardiovascular diseases and diabetes. In this review, we mainly discuss the function of UPRmt, describe the regulatory mechanisms of UPRmt in C. elegans and mammals, and summarize the relationship between UPRmt and various human diseases.
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Affiliation(s)
- Zixin Zhou
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, University of Chinese Academy of Sciences, Beijing, China
| | - Yumei Fan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Ruikai Zong
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Ke Tan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
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Mahmud SA, Qureshi MA, Pellegrino MW. On the offense and defense: mitochondrial recovery programs amidst targeted pathogenic assault. FEBS J 2022; 289:7014-7037. [PMID: 34270874 PMCID: PMC9192128 DOI: 10.1111/febs.16126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/24/2021] [Accepted: 07/15/2021] [Indexed: 01/13/2023]
Abstract
Bacterial pathogens employ a variety of tactics to persist in their host and promote infection. Pathogens often target host organelles in order to benefit their survival, either through manipulation or subversion of their function. Mitochondria are regularly targeted by bacterial pathogens owing to their diverse cellular roles, including energy production and regulation of programmed cell death. However, disruption of normal mitochondrial function during infection can be detrimental to cell viability because of their essential nature. In response, cells use multiple quality control programs to mitigate mitochondrial dysfunction and promote recovery. In this review, we will provide an overview of mitochondrial recovery programs including mitochondrial dynamics, the mitochondrial unfolded protein response (UPRmt ), and mitophagy. We will then discuss the various approaches used by bacterial pathogens to target mitochondria, which result in mitochondrial dysfunction. Lastly, we will discuss how cells leverage mitochondrial recovery programs beyond their role in organelle repair, to promote host defense against pathogen infection.
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Affiliation(s)
- Siraje A Mahmud
- Department of Biology, University of Texas Arlington, TX, USA
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Szczepanowska K, Trifunovic A. Mitochondrial matrix proteases: quality control and beyond. FEBS J 2022; 289:7128-7146. [PMID: 33971087 DOI: 10.1111/febs.15964] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/22/2021] [Accepted: 05/07/2021] [Indexed: 01/13/2023]
Abstract
To ensure correct function, mitochondria have developed several mechanisms of protein quality control (QC). Protein homeostasis highly relies on chaperones and proteases to maintain proper folding and remove damaged proteins that might otherwise form cell-toxic aggregates. Besides quality control, mitochondrial proteases modulate and regulate many essential functions, such as trafficking, processing and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy and apoptosis. Therefore, the impaired function of mitochondrial proteases is associated with various pathological conditions, including cancer, metabolic syndromes and neurodegenerative disorders. This review recapitulates and discusses the emerging roles of two major proteases of the mitochondrial matrix, LON and ClpXP. Although commonly acknowledge for their protein quality control role, recent advances have uncovered several highly regulated processes controlled by the LON and ClpXP connected to mitochondrial gene expression and respiratory chain function maintenance. Furthermore, both proteases have been lately recognized as potent targets for anticancer therapies, and we summarize those findings.
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Affiliation(s)
- Karolina Szczepanowska
- Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Germany
| | - Aleksandra Trifunovic
- Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Germany
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Savu DI, Moisoi N. Mitochondria - Nucleus communication in neurodegenerative disease. Who talks first, who talks louder? BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148588. [PMID: 35780856 DOI: 10.1016/j.bbabio.2022.148588] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 06/09/2022] [Accepted: 06/24/2022] [Indexed: 06/15/2023]
Abstract
Mitochondria - nuclear coadaptation has been central to eukaryotic evolution. The dynamic dialogue between the two compartments within the context of multiorganellar interactions is critical for maintaining cellular homeostasis and directing the balance survival-death in case of cellular stress. The conceptualisation of mitochondria - nucleus communication has so far been focused on the communication from the mitochondria under stress to the nucleus and the consequent signalling responses, as well as from the nucleus to mitochondria in the context of DNA damage and repair. During ageing processes this dialogue may be better viewed as an integrated bidirectional 'talk' with feedback loops that expand beyond these two organelles depending on physiological cues. Here we explore the current views on mitochondria - nucleus dialogue and its role in maintaining cellular health with a focus on brain cells and neurodegenerative disease. Thus, we detail the transcriptional responses initiated by mitochondrial dysfunction in order to protect itself and the general cellular homeostasis. Additionally, we are reviewing the knowledge of the stress pathways initiated by DNA damage which affect mitochondria homeostasis and we add the information provided by the study of combined mitochondrial and genotoxic damage. Finally, we reflect on how each organelle may take the lead in this dialogue in an ageing context where both compartments undergo accumulation of stress and damage and where, perhaps, even the communications' mechanisms may suffer interruptions.
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Affiliation(s)
- Diana Iulia Savu
- Department of Life and Environmental Physics, Horia Hulubei National Institute of Physics and Nuclear Engineering, Reactorului 30, P.O. Box MG-6, Magurele 077125, Romania
| | - Nicoleta Moisoi
- Leicester School of Pharmacy, Leicester Institute for Pharmaceutical Innovation, Faculty of Health Sciences, De Montfort University, The Gateway, Hawthorn Building 1.03, LE1 9BH Leicester, UK.
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Inigo JR, Chandra D. The mitochondrial unfolded protein response (UPR mt): shielding against toxicity to mitochondria in cancer. J Hematol Oncol 2022; 15:98. [PMID: 35864539 PMCID: PMC9306209 DOI: 10.1186/s13045-022-01317-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/11/2022] [Indexed: 12/20/2022] Open
Abstract
Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.
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Affiliation(s)
- Joseph R Inigo
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Dhyan Chandra
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Talaverón-Rey M, Suárez-Carrillo A, Munuera-Cabeza M, Reche-López D, Cilleros-Holgado P, Piñero-Pérez R, Sánchez-Alcázar JA. Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target? Biomedicines 2022; 10:1611. [PMID: 35884915 PMCID: PMC9313171 DOI: 10.3390/biomedicines10071611] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/18/2022] Open
Abstract
Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria's role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to this day. Therefore, new therapeutic approaches, such as activation of the mitochondrial unfolded protein response (UPRmt), are being examined. UPRmt englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPRmt activation, through an hormetic response, promotes cell homeostasis and improves lifespan and disease conditions in biological models of neurodegenerative diseases, cardiopathies, and mitochondrial diseases. Although UPRmt activation is a promising therapeutic option for many conditions, its overactivation could lead to non-desired side effects, such as increased heteroplasmy of mitochondrial DNA mutations or cancer progression in oncologic patients. In this review, we present the most recent UPRmt activation therapeutic strategies, UPRmt's role in diseases, and its possible negative consequences in particular pathological conditions.
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Affiliation(s)
- Juan M. Suárez-Rivero
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Carmen J. Pastor-Maldonado
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Suleva Povea-Cabello
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Mónica Álvarez-Córdoba
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Irene Villalón-García
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Marta Talaverón-Rey
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Alejandra Suárez-Carrillo
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Manuel Munuera-Cabeza
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Diana Reche-López
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Paula Cilleros-Holgado
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - Rocío Piñero-Pérez
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
| | - José A. Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013 Sevilla, Spain; (J.M.S.-R.); (C.J.P.-M.); (S.P.-C.); (M.Á.-C.); (I.V.-G.); (M.T.-R.); (A.S.-C.); (M.M.-C.); (D.R.-L.); (P.C.-H.); (R.P.-P.)
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013 Sevilla, Spain
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Jishi A, Qi X. Altered Mitochondrial Protein Homeostasis and Proteinopathies. Front Mol Neurosci 2022; 15:867935. [PMID: 35571369 PMCID: PMC9095842 DOI: 10.3389/fnmol.2022.867935] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/25/2022] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence implicates mitochondrial dysfunction as key in the development and progression of various forms of neurodegeneration. The multitude of functions carried out by mitochondria necessitates a tight regulation of protein import, dynamics, and turnover; this regulation is achieved via several, often overlapping pathways that function at different levels. The development of several major neurodegenerative diseases is associated with dysregulation of these pathways, and growing evidence suggests direct interactions between some pathogenic proteins and mitochondria. When these pathways are compromised, so is mitochondrial function, and the resulting deficits in bioenergetics, trafficking, and mitophagy can exacerbate pathogenic processes. In this review, we provide an overview of the regulatory mechanisms employed by mitochondria to maintain protein homeostasis and discuss the failure of these mechanisms in the context of several major proteinopathies.
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Affiliation(s)
| | - Xin Qi
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
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Tian H, Wang T, Zhang Y, Pan T, Yao S, Yu H, Ma K, Wang S. Astragaloside IV protects against C/EBP homologous protein-mediated apoptosis in oxidized low-density lipoprotein-treated macrophages by promoting autophagy. Eur J Pharmacol 2022; 923:174912. [PMID: 35339476 DOI: 10.1016/j.ejphar.2022.174912] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/19/2022] [Accepted: 03/19/2022] [Indexed: 11/03/2022]
Abstract
Astragaloside Ⅳ (AS-Ⅳ) is one of the main active components extracted from Astragalus membranaceus that exerts an antiatherosclerotic effect. Our study explored the underlying anti-apoptotic effects and the mechanisms of action of AS-Ⅳ in oxidized low-density lipoprotein (oxLDL)-stimulated macrophages and in vulnerable plaques. The results showed that AS-Ⅳ lowered the oxLDL-induced lipid content and reversed the oxLDL-induced reduction in cell viability and elevation in lactate dehydrogenase (LDH) leakage and apoptosis in RAW264.7 macrophages, similar to the effects of 4-phenylbutyric acid (PBA, an ER stress inhibitor). In addition, consistent with the effect exerted by PBA, AS-Ⅳ inhibited oxLDL-triggered ER stress activation by decreasing the level of inositol-requiring enzyme1 phosphorylation and transcription factor 6 nuclear translocation and upregulating the protein and mRNA expression of glucose-regulated protein 78 (GPR78) and C/EBP homologous protein (CHOP). As expected, autophagy activation was induced by AS-IV, evidenced by increased expression of microtubule-associated protein 1 light chain 3-Ⅱ (LC3-Ⅱ), autophagy-related gene 5, and beclin-1 in macrophages. Furthermore, after pretreatment with 3-methyladenine and beclin-1 small interfering RNA, the inhibitory role played by AS-Ⅳ in oxLDL-induced ER stress-CHOP-mediated macrophage apoptosis was weakened, while its inhibitory effect was further enhanced by rapamycin pretreatment. Moreover, administration of AS-Ⅳ or rapamycin to Apoe-/- mice upregulated LC3-Ⅱ expression and collagen content but decreased CHOP expression, macrophage apoptosis, and lipid areas. Overall, by promoting autophagy, AS-Ⅳ effectively protects macrophages from oxLDL-induced apoptosis mediated by ER stress-CHOP, which may reinforce the stability of atherosclerotic plaques.
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Affiliation(s)
- Hua Tian
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China; Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China.
| | - Tong Wang
- College of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China
| | - Yumei Zhang
- Department of Follow-up Visit, Binzhou People's Hospital Affiliated to Shandong First Medical University & Shandong Academy of Medical Sciences, Binzhou, 256610, Shandong, China
| | - Tianqi Pan
- College of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China
| | - Shutong Yao
- College of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China
| | - Huayun Yu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China
| | - Ke Ma
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China
| | - Shijun Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China.
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38
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Yim J, Park SB. Label-Free Target Identification Reveals the Anticancer Mechanism of a Rhenium Isonitrile Complex. Front Chem 2022; 10:850638. [PMID: 35372261 PMCID: PMC8964423 DOI: 10.3389/fchem.2022.850638] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/25/2022] [Indexed: 01/21/2023] Open
Abstract
Elucidation of the molecular mechanism of therapeutic agents and potential candidates is in high demand. Interestingly, rhenium-based complexes have shown a highly selective anticancer effect, only on cancer cells, unlike platinum-based drugs, such as cisplatin and carboplatin. These differences might be attributed to their different molecular targets. We confirmed that the target of tricarbonyl rhenium isonitrile polypyridyl (TRIP) complex is a protein, not DNA, using ICP-MS analysis and identified heat shock protein 60 (HSP60) as its target protein using a label-free target identification method. The subsequent biological evaluation revealed that TRIP directly inhibits the chaperone function of HSP60 and induces the accumulation of misfolded proteins in mitochondria, thereby leading to the activation of mitochondrial unfolded protein response (mtUPR)-mediated JNK2/AP-1/CHOP apoptotic pathway.
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Affiliation(s)
- Junhyeong Yim
- Department of Biophysics and Chemical Biology, Seoul National University, Seoul, South Korea
| | - Seung Bum Park
- Department of Biophysics and Chemical Biology, Seoul National University, Seoul, South Korea
- CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, South Korea
- *Correspondence: Seung Bum Park,
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Wodrich APK, Scott AW, Shukla AK, Harris BT, Giniger E. The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations. Front Mol Neurosci 2022; 15:831116. [PMID: 35283733 PMCID: PMC8914544 DOI: 10.3389/fnmol.2022.831116] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/26/2022] [Indexed: 12/11/2022] Open
Abstract
Aging and age-related neurodegeneration are both associated with the accumulation of unfolded and abnormally folded proteins, highlighting the importance of protein homeostasis (termed proteostasis) in maintaining organismal health. To this end, two cellular compartments with essential protein folding functions, the endoplasmic reticulum (ER) and the mitochondria, are equipped with unique protein stress responses, known as the ER unfolded protein response (UPR ER ) and the mitochondrial UPR (UPR mt ), respectively. These organellar UPRs play roles in shaping the cellular responses to proteostatic stress that occurs in aging and age-related neurodegeneration. The loss of adaptive UPR ER and UPR mt signaling potency with age contributes to a feed-forward cycle of increasing protein stress and cellular dysfunction. Likewise, UPR ER and UPR mt signaling is often altered in age-related neurodegenerative diseases; however, whether these changes counteract or contribute to the disease pathology appears to be context dependent. Intriguingly, altering organellar UPR signaling in animal models can reduce the pathological consequences of aging and neurodegeneration which has prompted clinical investigations of UPR signaling modulators as therapeutics. Here, we review the physiology of both the UPR ER and the UPR mt , discuss how UPR ER and UPR mt signaling changes in the context of aging and neurodegeneration, and highlight therapeutic strategies targeting the UPR ER and UPR mt that may improve human health.
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Affiliation(s)
- Andrew P. K. Wodrich
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
- Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, United States
- College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Andrew W. Scott
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Arvind Kumar Shukla
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Brent T. Harris
- Department of Pathology, Georgetown University, Washington, DC, United States
- Department of Neurology, Georgetown University, Washington, DC, United States
| | - Edward Giniger
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
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Wang G, Fan Y, Cao P, Tan K. Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges. Cell Biosci 2022; 12:18. [PMID: 35180892 PMCID: PMC8857832 DOI: 10.1186/s13578-022-00747-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/18/2022] [Indexed: 02/08/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved protective transcriptional response that maintains mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases in response to various stresses. The UPRmt-mediated transcriptional program requires the participation of various upstream signaling pathways and molecules. The factors regulating the UPRmt in Caenorhabditis elegans (C. elegans) and mammals are both similar and different. Cancer cells, as malignant cells with uncontrolled proliferation, are exposed to various challenges from endogenous and exogenous stresses. Therefore, in cancer cells, the UPRmt is hijacked and exploited for the repair of mitochondria and the promotion of tumor growth, invasion and metastasis. In this review, we systematically introduce the inducers of UPRmt, the biological processes in which UPRmt participates, the mechanisms regulating the UPRmt in C. elegans and mammals, cross-tissue signal transduction of the UPRmt and the roles of the UPRmt in promoting cancer initiation and progression. Disrupting proteostasis in cancer cells by targeting UPRmt constitutes a novel anticancer therapeutic strategy.
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Affiliation(s)
- Ge Wang
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China.,Department of Human Anatomy, Histology and Embryology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China
| | - Yumei Fan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China
| | - Pengxiu Cao
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China
| | - Ke Tan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Hebei, 050024, China.
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41
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Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis. Int J Mol Sci 2021; 23:ijms23010007. [PMID: 35008433 PMCID: PMC8745001 DOI: 10.3390/ijms23010007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.
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Hu D, Liu Z, Qi X. Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases? Front Neurosci 2021; 15:746873. [PMID: 34867159 PMCID: PMC8633545 DOI: 10.3389/fnins.2021.746873] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/19/2021] [Indexed: 12/30/2022] Open
Abstract
Many lines of evidence have indicated the therapeutic potential of rescuing mitochondrial integrity by targeting specific mitochondrial quality control pathways in neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. In addition to ATP synthesis, mitochondria are critical regulators of ROS production, lipid metabolism, calcium buffering, and cell death. The mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy are the three main quality control mechanisms responsible for maintaining mitochondrial proteostasis and bioenergetics. The proper functioning of these complex processes is necessary to surveil and restore mitochondrial homeostasis and the healthy pool of mitochondria in cells. Mitochondrial dysfunction occurs early and causally in disease pathogenesis. A significant accumulation of mitochondrial damage resulting from compromised quality control pathways leads to the development of neuropathology. Moreover, genetic or pharmaceutical manipulation targeting the mitochondrial quality control mechanisms can sufficiently rescue mitochondrial integrity and ameliorate disease progression. Thus, therapies that can improve mitochondrial quality control have great promise for the treatment of neurodegenerative diseases. In this review, we summarize recent progress in the field that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases. We also discuss the translational approaches targeting mitochondrial function, with a focus on the restoration of mitochondrial integrity, including mitochondrial dynamics, mitophagy, and mitochondrial proteostasis.
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Affiliation(s)
- Di Hu
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Zunren Liu
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Xin Qi
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Center for Mitochondrial Disease, Case Western Reserve University School of Medicine, Cleveland, OH, United States
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Huo H, Wang S, Bai Y, Liao J, Li X, Zhang H, Han Q, Hu L, Pan J, Li Y, Tang Z, Guo J. Copper exposure induces mitochondrial dynamic disorder and oxidative stress via mitochondrial unfolded protein response in pig fundic gland. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 223:112587. [PMID: 34352579 DOI: 10.1016/j.ecoenv.2021.112587] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 06/13/2023]
Abstract
Cu is a metallic element that widely spread over in the environment, which have raised wide concerns about the potential toxic effects and public health threat. The objective of this study aimed to investigate the impression of copper (Cu)-triggered toxicity on mitochondrial dynamic, oxidative stress, and unfolded protein response (UPRmt) in fundic gland of pigs. Weaned pigs were randomly distributed into three groups, fed with different Cu of 10 mg/kg (control group), 125 mg/kg (group I), and 250 mg/kg (group Ⅱ). The trial persisted for 80 days and the fundic gland tissues were collected for further researches. Moreover, the markers participated to mitochondrial dynamic, UPRmt，and oxidative stress in fundic gland were determined. Results revealed that vacuolar degeneration were observed in the treated groups contrast with control group, and the Cu level was boosted with the increasing intake of Cu. Besides that, the levels of CAT, TRX, H2O2, and G6PDH were reduced in group Ⅰ and group Ⅱ, the mRNA levels of NRF2, HO-1, SOD-1, CAT, SOD-2, GSR, GPX1, GPX4, and TRX in the treated groups were promoted contrast to control group. Furthermore, the protein expression of KEAP1 was dramatically decreased, and the protein expression of NRF2, TRX and HO-1 were markedly enhanced in group Ⅰ and Ⅱ at 80 days. Moreover, the mRNA and protein expression levels of MFN1, MFN2, and OPA1 down-regulated and protein level of DRP1 was increased with the adding levels of Cu. Nevertheless, the UPRmt-related mRNA levels of CLPP, HTRA-2, CHOP, HSP10, and HSP60 were enhanced dramatically in Cu treatment group compared with control group. In general, our current study demonstrated that excessive absorption of Cu in fundic gland were related with stimulating UPRmt, oxidative stress, and the NRF2 interceded antioxidant defense. These results could afford an updated evidence on molecular theory of Cu-invited toxicity.
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Affiliation(s)
- Haihua Huo
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Shuzhou Wang
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Yuman Bai
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Jianzhao Liao
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Xinrun Li
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Hui Zhang
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Qingyue Han
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Lianmei Hu
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Jiaqiang Pan
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China
| | - Ying Li
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China.
| | - Zhaoxin Tang
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China.
| | - Jianying Guo
- College of Veterinary Medicine, South China Agriculture University, Guangzhou 510642, Guangdong, PR China.
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Della-Flora Nunes G, Wilson ER, Hurley E, He B, O'Malley BW, Poitelon Y, Wrabetz L, Feltri ML. Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination. eLife 2021; 10:e66278. [PMID: 34519641 PMCID: PMC8478418 DOI: 10.7554/elife.66278] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 09/13/2021] [Indexed: 12/26/2022] Open
Abstract
Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.
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Affiliation(s)
- Gustavo Della-Flora Nunes
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
| | - Emma R Wilson
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
| | - Edward Hurley
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
| | - Bin He
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist HospitalHoustonUnited States
| | - Bert W O'Malley
- Department of Medicine and Molecular and Cellular Biology, Baylor College of MedicineHoustonUnited States
| | - Yannick Poitelon
- Department of Neuroscience and Experimental Therapeutics, Albany Medical CollegeAlbanyUnited States
| | - Lawrence Wrabetz
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
- Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at BuffaloBuffaloUnited States
| | - M Laura Feltri
- Hunter James Kelly Research Institute, University at BuffaloBuffaloUnited States
- Department of Biochemistry, University at BuffaloBuffaloUnited States
- Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at BuffaloBuffaloUnited States
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Shastri S, Shinde T, Woolley KL, Smith JA, Gueven N, Eri R. Short-Chain Naphthoquinone Protects Against Both Acute and Spontaneous Chronic Murine Colitis by Alleviating Inflammatory Responses. Front Pharmacol 2021; 12:709973. [PMID: 34497514 PMCID: PMC8419285 DOI: 10.3389/fphar.2021.709973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is characterised by chronic, relapsing, idiopathic, and multifactorial colon inflammation. Recent evidence suggests that mitochondrial dysfunction plays a critical role in the onset and recurrence of this disease. Previous reports highlighted the potential of short-chain quinones (SCQs) for the treatment of mitochondrial dysfunction due to their reversible redox characteristics. We hypothesised that a recently described potent mitoprotective SCQ (UTA77) could ameliorate UC symptoms and pathology. In a dextran sodium sulphate- (DSS-) induced acute colitis model in C57BL/6J mice, UTA77 substantially improved DSS-induced body weight loss, disease activity index (DAI), colon length, and histopathology. UTA77 administration also significantly increased the expression of tight junction (TJ) proteins occludin and zona-occludin 1 (ZO-1), which preserved intestinal barrier integrity. Similar responses were observed in the spontaneous Winnie model of chronic colitis, where UTA77 significantly improved DAI, colon length, and histopathology. Furthermore, UTA77 potently suppressed elevated levels of proinflammatory cytokines and chemokines in colonic explants of both DSS-treated and Winnie mice. These results strongly suggest that UTA77 or its derivatives could be a promising novel therapeutic approach for the treatment of human UC.
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Affiliation(s)
- Sonia Shastri
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Tanvi Shinde
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia.,Centre for Food Innovation, Tasmanian Institute of Agriculture, University of Tasmania, Launceston, TAS, Australia
| | - Krystel L Woolley
- School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS, Australia
| | - Jason A Smith
- School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS, Australia
| | - Nuri Gueven
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Rajaraman Eri
- Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
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Jenkins EC, Chattopadhyay M, Germain D. Are the estrogen receptor and SIRT3 axes of the mitochondrial UPR key regulators of breast cancer sub-type determination according to age? AGING AND CANCER 2021; 2:75-81. [PMID: 34927079 DOI: 10.1002/aac2.12035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Aging is a major risk factor of developing breast cancer. Despite the fact that post-menopausal women have lower levels of estrogen, older women have a higher rate of estrogen receptor alpha (ERα) positive breast cancer. Conversely, young women who have elevated levels of estrogen tend to develop ERα negative disease that is associated with higher rate of metastasis. This perspective proposes a unifying model centered around the importance of mitochondrial biology in cancer and aging to explain these observations. Mitochondria are essential for the survival of cancer cells and therefore pathways that maintain the functionality of the mitochondrial network in cancer cells fulfill a critical role in the survival of cancer cells. The ERα and the mitochondrial sirtuin-3 (SIRT3) have been reported to be key players of the mitochondrial unfolded protein response (UPRmt) 1-5. The UPRmt is a complex retrograde signaling cascade that regulates the communication between the mitochondria and the nucleus to restore mitochondrial fitness in response to oxidative stress 5-7. SIRT3 is a major regulator of aging 8. Its level decreases with age and single nucleotide polymorphisms (SNPs) that preserve its expression at higher levels are observed in centenarians 9,10. We propose a model whereby the ERα axis of the UPRmt acts to compensate for the loss of SIRT3 observed with age, and becomes the dominant axis of the UPRmt to maintain the integrity of the mitochondria during transformation, thus explaining the selective advantage of ERα positive luminal cells in breast cancer arising from older women.
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Affiliation(s)
- Edmund Charles Jenkins
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Department of Medicine, Division of Hematology/Oncology, New York, 10029, NY, USA
| | - Mrittika Chattopadhyay
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Department of Medicine, Division of Hematology/Oncology, New York, 10029, NY, USA
| | - Doris Germain
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Department of Medicine, Division of Hematology/Oncology, New York, 10029, NY, USA
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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Shangguan F, Zhou H, Ma N, Wu S, Huang H, Jin G, Wu S, Hong W, Zhuang W, Xia H, Lan L. A Novel Mechanism of Cannabidiol in Suppressing Hepatocellular Carcinoma by Inducing GSDME Dependent Pyroptosis. Front Cell Dev Biol 2021; 9:697832. [PMID: 34350183 PMCID: PMC8327166 DOI: 10.3389/fcell.2021.697832] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/14/2021] [Indexed: 12/20/2022] Open
Abstract
Cannabidiol (CBD), a phytochemical derived from Cannabis sativa L., has been demonstrated to exhibit promising anti-tumor properties in multiple cancer types. However, the effects of CBD on hepatocellular carcinoma (HCC) cells remain unknown. We have shown that CBD effectively suppresses HCC cell growth in vivo and in vitro, and induced HCC cell pyroptosis in a caspase-3/GSDME-dependent manner. We further demonstrated that accumulation of integrative stress response (ISR) and mitochondrial stress may contribute to the initiation of pyroptotic signaling by CBD. Simultaneously, CBD can repress aerobic glycolysis through modulation of the ATF4-IGFBP1-Akt axis, due to the depletion of ATP and crucial intermediate metabolites. Collectively, these observations indicate that CBD could be considered as a potential compound for HCC therapy.
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Affiliation(s)
- Fugen Shangguan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongfei Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Nengfang Ma
- School of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Shanshan Wu
- Medical Research Center, The First Affliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huimin Huang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guihua Jin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shijia Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Weilong Hong
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Weiwei Zhuang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongping Xia
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Pathology in the School of Basic Medical Sciences, The Affiliated Sir Run Run Hospital, State Key Laboratory of Reproductive Medicine, Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing, China
| | - Linhua Lan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Mitochondria and Antibiotics: For Good or for Evil? Biomolecules 2021; 11:biom11071050. [PMID: 34356674 PMCID: PMC8301944 DOI: 10.3390/biom11071050] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 01/16/2023] Open
Abstract
The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.
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Sensing, signaling and surviving mitochondrial stress. Cell Mol Life Sci 2021; 78:5925-5951. [PMID: 34228161 PMCID: PMC8316193 DOI: 10.1007/s00018-021-03887-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022]
Abstract
Mitochondrial fidelity is a key determinant of longevity and was found to be perturbed in a multitude of disease contexts ranging from neurodegeneration to heart failure. Tight homeostatic control of the mitochondrial proteome is a crucial aspect of mitochondrial function, which is severely complicated by the evolutionary origin and resulting peculiarities of the organelle. This is, on one hand, reflected by a range of basal quality control factors such as mitochondria-resident chaperones and proteases, that assist in import and folding of precursors as well as removal of aggregated proteins. On the other hand, stress causes the activation of several additional mechanisms that counteract any damage that may threaten mitochondrial function. Countermeasures depend on the location and intensity of the stress and on a range of factors that are equipped to sense and signal the nature of the encountered perturbation. Defective mitochondrial import activates mechanisms that combat the accumulation of precursors in the cytosol and the import pore. To resolve proteotoxic stress in the organelle interior, mitochondria depend on nuclear transcriptional programs, such as the mitochondrial unfolded protein response and the integrated stress response. If organelle damage is too severe, mitochondria signal for their own destruction in a process termed mitophagy, thereby preventing further harm to the mitochondrial network and allowing the cell to salvage their biological building blocks. Here, we provide an overview of how different types and intensities of stress activate distinct pathways aimed at preserving mitochondrial fidelity.
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