1
|
Budgude P, Kale V, Vaidya A. Microvesicles and exosomes isolated from murine bone marrow-derived mesenchymal stromal cells primed with p38MAPK inhibitor differentially regulate hematopoietic stem cell function. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2025; 53:122-137. [PMID: 40062630 DOI: 10.1080/21691401.2025.2475095] [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: 10/24/2024] [Revised: 01/07/2025] [Accepted: 02/27/2025] [Indexed: 05/13/2025]
Abstract
The signaling mechanisms active within mesenchymal stromal cells (MSCs) influence the composition of microvesicles (MVs) and exosomes (Exos) secreted by them. Previously, we showed that priming MSCs with a p38 pharmacological inhibitor (pMSCs) rejuvenates them and improves their ability to promote ex vivo hematopoietic stem cell (HSC) expansion. This study examined whether pMSCs exerted HSC-supportive ability via MVs (pMVs) and Exos (pExos). Our findings demonstrate distinct regulation of HSC fate by pMVs and pExos. pMVs promoted the expansion of long-term HSCs (LT-HSCs), distinguished by their robust self-renewal capacity and superior engraftment ability. In contrast, pExos facilitated expansion of short-term HSCs (ST-HSCs) with high proliferative and differentiation potential. Infusing a combination of pMVs- and pExos-expanded HSCs as a composite graft resulted in significantly higher HSC engraftment, emphasizing the synergistic interaction between LT- and ST-HSC populations. Gene expression studies, functional and phenotypic experiments showed that pMVs regulate HSC quiescence via the Egr1/Cdkn1a axis, while pExos control HSC proliferation via the Nfya/Cdkn1a axis. These findings provide insights into the molecular mechanisms underlying the differential regulation of HSC function by pMVs and pExos. It also proposes a composite graft strategy of using pMVs and pExos as "MSC-derived biologics" for improving the HSC transplantation success.
Collapse
Affiliation(s)
- Pallavi Budgude
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
| | - Anuradha Vaidya
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
| |
Collapse
|
2
|
Parchwani D, Singh R, Patel D. Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance. World J Methodol 2025; 15:102709. [DOI: 10.5662/wjm.v15.i3.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 03/06/2025] Open
Abstract
The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.
Collapse
Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Digisha Patel
- Department of Physiology, Shantabaa Medical College and General Hospital Amreli, Amreli 365601, Gujarāt, India
| |
Collapse
|
3
|
Bezrukova AI, Basharova KS, Emelyanov AK, Rybakov AV, Miliukhina IV, Pchelina SN, Usenko TS. Autophagy Process in Parkinson's Disease Depends on Mutations in the GBA1 and LRRK2 Genes. Biochem Genet 2025:10.1007/s10528-025-11125-z. [PMID: 40388077 DOI: 10.1007/s10528-025-11125-z] [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: 01/09/2025] [Accepted: 04/28/2025] [Indexed: 05/20/2025]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and abnormal aggregation of the alpha-synuclein protein. Disruption of the autophagy-lysosomal pathway is closely associated with PD pathogenesis. Here, using western-blot analysis we assessed the level of autophagy-related proteins, including phosphorylated mTOR (p-mTOR), phosphorylated RPS6 (p-RPS6), beclin-1 (BECN1), LC3B, p62, and cathepsin D (CTSD) in macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages) of GBA1-PD (p.N370S/N, p.L444P/N), LRRK2-PD (p.G2019S/N), idiopathic PD (iPD) patients, and healthy controls. Our findings revealed mutation-specific disruptions in autophagy pathways among PD patients. In p.N370S-GBA1-PD, PBMC-derived macrophages exhibited elevated levels of p-RPS6, BECN1, LC3B-II and decreased mature form of CTSD levels suggesting more active mTOR-dependent autophagy initiation alongside potential autophagosome accumulation that may lead to downregulation of lysosomal degradation. p.L444P-GBA1-PD PBMC-derived macrophages showed increased levels of p-RPS6 and BECN1, coupled with decreased p62 levels and stable mature form of CTSD and LC3B-II, indicative of enhanced autophagy flux driven by mTOR activity without evident lysosomal dysfunction. In p.G2019S-LRRK2-PD patients, PBMC-derived macrophages demonstrated elevated p-RPS6, LC3B-II, and mature CTSD levels, alongside reduced p62 levels. These changes suggest higher basal autophagosome abundance in steady-state autophagy and turnover, potentially driven by lysosomal alterations rather than direct mTOR dysregulation. These mutation-dependent differences highlight distinct autophagy dynamics in GBA1-PD and LRRK2-PD, underscoring the critical role of genetic mutations in modulating PD pathogenesis. Our results emphasize the necessity for subtype-specific therapeutic strategies targeting autophagy and other mTOR-regulated pathways to address the heterogeneity of PD mechanisms.
Collapse
Affiliation(s)
- A I Bezrukova
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - K S Basharova
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - A K Emelyanov
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - A V Rybakov
- Institute of the Human Brain, Russian Academy of Sciences (RAS), 9 Akademika Pavlova Street, Saint Petersburg, Russia
| | - I V Miliukhina
- Institute of the Human Brain, Russian Academy of Sciences (RAS), 9 Akademika Pavlova Street, Saint Petersburg, Russia
| | - S N Pchelina
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - T S Usenko
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia.
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia.
| |
Collapse
|
4
|
Geng Q, Jiao Y, Diao W, Xu J, Wang Z, Wang X, Wang Z, Zhao L, Yang L, Wang Y, Deng T, Wang B, Xiao C. IGF2BP3-mediated m 6A modification of RASGRF1 promoting joint injury in rheumatoid arthritis. Bone Res 2025; 13:51. [PMID: 40355406 PMCID: PMC12069659 DOI: 10.1038/s41413-025-00434-z] [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: 08/26/2024] [Revised: 03/16/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025] Open
Abstract
With the deepening of epigenetic research, studies have shown that N6-methyladenosine (m6A) is closely related to the development of rheumatoid arthritis (RA), but the mechanism is still unclear. In the study, we collected synovial tissues from normal controls and patients with osteoarthritis (OA) or RA. The levels of m6A and inflammation were analyzed by immunofluorescence staining and western blotting. The roles of IGF2BP3 in cell proliferation and inflammatory activation were explored using transfection and RNA immunoprecipitation assays. IGF2BP3-/- mice were generated and used to establish an arthritis mouse model by transferring serum from adult arthritis K/BxN mice. We found m6A levels were markedly increased in RA patients and mouse models, and the expression of IGF2BP3 was upregulated in individuals with RA and related to the levels of inflammatory markers. IGF2BP3 played an important part in RA-fibroblast-like synoviocytes (FLS) by promoting cell proliferation, migration, invasion, inflammatory cytokine release and inhibiting autophagy. In addition, IGF2BP3 inhibited autophagy to reduce ROS production, thereby decreasing the inflammatory activation of macrophages. More importantly, RASGRF1-mediated mTORC1 activation played a crucial role in the ability of IGF2BP3 to promote cell proliferation and inflammatory activation. In an arthritis model of IGF2BP3-/- mice, IGF2BP3 knockout inhibited RA-FLS proliferation and inflammatory infiltration, and further ameliorated RA joint injury. Our study revealed an important role for IGF2BP3 in RA progression. The targeted inhibition of IGF2BP3 reduced cell proliferation and inflammatory activation and limited RA development, providing a potential strategy for RA therapy.
Collapse
Affiliation(s)
- Qishun Geng
- China-Japan Friendship Clinical Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yi Jiao
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital Clinical Medicine, Beijing, China
| | - Wenya Diao
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital Clinical Medicine, Beijing, China
| | - Jiahe Xu
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Zhaoran Wang
- China-Japan Friendship Clinical Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xing Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital Clinical Medicine, Beijing, China
| | - Zihan Wang
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital Clinical Medicine, Beijing, China
- Department of TCM Rheumatology, China-Japan Friendship Hospital, Beijing, China
| | - Lu Zhao
- China-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Lei Yang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Yilin Wang
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Tingting Deng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
| | - Bailiang Wang
- Department of Orthopaedic Surgery, China-Japan Friendship Hospital, Beijing, China.
| | - Cheng Xiao
- China-Japan Friendship Clinical Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
- Department of Emergency, China-Japan Friendship Hospital, Beijing, China.
| |
Collapse
|
5
|
Xu M, Xu B. Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics. Mol Cancer 2025; 24:138. [PMID: 40335986 PMCID: PMC12057185 DOI: 10.1186/s12943-025-02309-7] [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: 11/27/2024] [Accepted: 03/18/2025] [Indexed: 05/09/2025] Open
Abstract
Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.
Collapse
Affiliation(s)
- Mengke Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Intelligent Oncology Innovation Center Designated by the Ministry of Education, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Intelligent Oncology Innovation Center Designated by the Ministry of Education, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China.
| |
Collapse
|
6
|
Seo MK, Kim H, Choi AJ, Seog DH, Kho WG, Park SW, Lee JG. Effects of tianeptine on mTORC1-mediated neuronal autophagy in primary rat hippocampal neurons under nutrient deprivation. Sci Rep 2025; 15:14488. [PMID: 40280952 PMCID: PMC12032415 DOI: 10.1038/s41598-025-92988-5] [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: 12/07/2024] [Accepted: 03/04/2025] [Indexed: 04/29/2025] Open
Abstract
The aim of this study was to investigate the effects of the antidepressant tianeptine on the mechanistic target of rapamycin complex 1(mTORC1)-mediated autophagy pathway in primary hippocampal neurons exposed to B27-deprived conditions. When primary hippocampal neurons were treated with tianeptine at doses of 1, 10, 50, and 100 µM for 3 days under B27-deprived conditions, we observed that it activated autophagy and increased the formation of autophagosomes through the upregulation of autophagic proteins, including autophagy-activating kinase 1 (ULK1), Beclin 1, LC3B-II/I, and p62. And at a concentration of 100 µM tianeptine, the decrease in mTORC1 phosphorylation induced by B27 deprivation was significantly reversed. Changes in the expression of autophagic proteins induced by B27 deprivation were reversed by tianeptine treatment in a concentration-dependent manner, and tianeptine significantly reduced the increase in LC3B membrane number induced by B27 deprivation, an effect that was blocked by pretreatment with rapamycin. In conclusion, tianeptine attenuated the activity of mTORC1-mediated autophagy in primary rat hippocampal neurons under B27-deprived conditions. These results may suggest a novel mechanism by which tianeptine may affect autophagy in neurons.
Collapse
Affiliation(s)
- Mi Kyoung Seo
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Hyewon Kim
- Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, 48108, Republic of Korea
| | - Ah Jeong Choi
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
| | - Dae-Hyun Seog
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea
- Department of Biochemistry, College of Medicine, Inje University, Busan, 47392, Republic of Korea
- Dementia and Neurodegenerative Disease Research Center, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Weon-Gyu Kho
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
- Department of Parasitology, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Sung Woo Park
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea.
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea.
| | - Jung Goo Lee
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea.
- Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, 48108, Republic of Korea.
| |
Collapse
|
7
|
Wu F, Li C, Song X, Xie L. LAPTM5 confers cisplatin resistance in NSCLC by suppressing LAMP1 ubiquitination to stabilize lysosomal membranes and sustain autophagic flux. Cell Signal 2025; 132:111834. [PMID: 40280227 DOI: 10.1016/j.cellsig.2025.111834] [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: 02/14/2025] [Revised: 04/11/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Cisplatin is a widely used chemotherapeutic agent in the treatment of non-small cell lung cancer (NSCLC), but cisplatin resistance remains a significant clinical challenge. Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal membrane protein implicated in macroautophagy/autophagy, although its precise mechanism has yet to be fully elucidated.In this study, we demonstrated that LAPTM5 promotes cisplatin resistance in NSCLC by maintaining lysosomal membrane stability and preserving autophagic flux. Mechanistic investigations showed that LAPTM5 competes with LAMP1 for binding to WWP2, thereby inhibiting LAMP1 ubiquitination and degradation, which ultimately preserves lysosomal membrane stability. LAPTM5 knockdown increases lysosomal membrane permeability, leading to the release of cathepsin D (CTSD), which elevates intracellular reactive oxygen species (ROS) levels; further destabilizing the lysosomal membrane and accelerating cell death. Our findings elucidate the mechanism by which LAPTM5 contributes to cisplatin resistance through lysosomal membrane stabilization and identify LAPTM5 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC.
Collapse
Affiliation(s)
- Fan Wu
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Chunlan Li
- Department of Pharmacy and Shandong Provincinal key Traditional Chinese Medical Discipline of Clinical Chinese pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, China
| | - Xianrang Song
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
| | - Li Xie
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
| |
Collapse
|
8
|
Bubb K, Etich J, Probst K, Parashar T, Schuetter M, Dethloff F, Reincke S, Nolte JL, Krüger M, Schlötzer-Schrehard U, Nüchel J, Demetriades C, Giavalisco P, Riemer J, Brachvogel B. Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging. SCIENCE ADVANCES 2025; 11:eads1842. [PMID: 40249823 PMCID: PMC12007575 DOI: 10.1126/sciadv.ads1842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 03/14/2025] [Indexed: 04/20/2025]
Abstract
Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.
Collapse
Affiliation(s)
- Kristina Bubb
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Julia Etich
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Kristina Probst
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Tanvi Parashar
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Maximilian Schuetter
- Metabolic Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Frederik Dethloff
- Metabolic Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Susanna Reincke
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Janica L. Nolte
- Institute of Genetics, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Marcus Krüger
- Institute of Genetics, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Ursula Schlötzer-Schrehard
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Julian Nüchel
- Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany
| | - Constantinos Demetriades
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Max Planck Institute for Biology of Ageing (MPI-AGE), Cologne, Germany
| | - Patrick Giavalisco
- Metabolic Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Jan Riemer
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Institute of Biochemistry, Redox Biochemistry, University of Cologne, Cologne, Germany
| | - Bent Brachvogel
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| |
Collapse
|
9
|
Amponsah PS, Storchová Z. The proteostasis burden of aneuploidy. Biol Chem 2025:hsz-2024-0163. [PMID: 40221883 DOI: 10.1515/hsz-2024-0163] [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: 12/20/2024] [Accepted: 03/27/2025] [Indexed: 04/15/2025]
Abstract
Aneuploidy refers to chromosome number abnormality that is not an exact multiple of the haploid chromosome set. Aneuploidy has largely negative consequences in cells and organisms, manifested as so-called aneuploidy-associated stresses. A major consequence of aneuploidy is proteotoxic stress due to abnormal protein expression from imbalanced chromosome numbers. Recent advances have improved our understanding of the nature of the proteostasis imbalance caused by aneuploidy and highlighted their relevance with respect to organellar homeostasis, dosage compensation, or mechanisms employed by cells to mitigate the detrimental stress. In this review, we highlight the recent findings and outline questions to be addressed in future research.
Collapse
Affiliation(s)
- Prince Saforo Amponsah
- Group Proteostasis and Genomic Stability, RPTU Kaiserslautern-Landau, Paul-Ehrlich-Straße 24, D-67663 Kaiserslautern, Germany
- Department of Molecular Genetics, RPTU Kaiserslautern-Landau, D-67663 Kaiserslautern, Germany
| | - Zuzana Storchová
- Department of Molecular Genetics, RPTU Kaiserslautern-Landau, D-67663 Kaiserslautern, Germany
| |
Collapse
|
10
|
Nam H, Han J, Yu J, Cho C, Kim D, Kim Y, Kim M, Kim J, Jo D, Bae S. Autophagy induction enhances homologous recombination-associated CRISPR-Cas9 gene editing. Nucleic Acids Res 2025; 53:gkaf258. [PMID: 40239991 PMCID: PMC11997770 DOI: 10.1093/nar/gkaf258] [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: 07/25/2024] [Revised: 02/24/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9)-based gene editing via homologous recombination (HR) enables precise gene correction and insertion. However, its low efficiency poses a challenge due to the predominance of nonhomologous end-joining during DNA repair processes. Although numerous efforts have been made to boost HR efficiency, there remains a critical need to devise a novel method that can be universally applied across cell types and in vivo animals, which could ultimately facilitate therapeutic treatments. This study demonstrated that autophagy induction using different protocols, including nutrient deprivation or chemical treatment, significantly improved HR-associated gene editing at diverse genomic loci in mammalian cells. Notably, interacting cofactor proteins that bind to Cas9 under the autophagic condition have been identified, and autophagy induction could also enhance in vivo HR-associated gene editing in mice. These findings pave the way for effective gene correction or insertion for in vivo therapeutic treatments.
Collapse
Affiliation(s)
- Hye Jin Nam
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Jun Hee Han
- Department of Chemistry, Hanyang University, Seoul 04673, Republic of Korea
| | - Jihyeon Yu
- Medical Research Center of Genomic Medicine Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Chang Sik Cho
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University, Seoul 03080, Republic of Korea
| | - Dongha Kim
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Young Eun Kim
- Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea
| | - Min Ji Kim
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
- Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Jeong Hun Kim
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University, Seoul 03080, Republic of Korea
- Global Excellence Center for Gene & Cell Therapy (GEC-GCT), Seoul National University Hospital, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Dong Hyun Jo
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sangsu Bae
- Medical Research Center of Genomic Medicine Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| |
Collapse
|
11
|
Dilger OB, Carstens MF, Bothun CE, Payne AN, Berry DJ, Sanchez-Sotelo J, Morrey ME, Thaler R, Dudakovic A, Abdel MP. Induction of cellular autophagy impairs TGF-β1-mediated extracellular matrix deposition in primary human knee fibroblasts. Bone Joint Res 2025; 14:331-340. [PMID: 40192622 PMCID: PMC11975063 DOI: 10.1302/2046-3758.144.bjr-2024-0312.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/09/2025] Open
Abstract
Aims To evaluate the role of autophagy in primary knee fibroblasts undergoing myofibroblast differentiation as an in vitro model of arthrofibrosis, a complication after total knee arthroplasty characterized by aberrant intra-articular scar tissue formation and limited range of motion. Methods We conducted a therapeutic screen of autophagic-modulating therapies in primary human knee fibroblasts undergoing transforming growth factor-beta 1 (TGF-β1)-mediated myofibroblast differentiation. Autophagy was induced pharmacologically with rapamycin or by amino acid deprivation. Picrosirius red staining was performed to quantify collagen deposition. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were conducted to evaluate fibrotic gene expression levels. Results Rapamycin, an mTOR complex 1 (mTORC1) inhibitor and autophagy inducer, reduced TGF-β1-mediated collagen deposition. Interestingly, we simultaneously report that myofibrogenic genes, including ACTA2, were highly upregulated following rapamycin-TGF-β1 treatment. When autophagy was induced through amino acid deprivation, we demonstrated suppressed extracellular matrix levels, fibrotic gene expression (e.g. ACTA2), and SMAD2 phosphorylation levels in TGF-β1-stimulated fibroblasts. Conclusion Our findings demonstrate that the induction of cellular autophagy suppresses TGF-β1-induced collagen deposition in primary human knee fibroblasts. Taken together, these data suggest that cellular autophagy may be prophylactic against the pathogenesis of arthrofibrosis.
Collapse
Affiliation(s)
- Oliver B. Dilger
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Mason F. Carstens
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Cole E. Bothun
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Ashley N. Payne
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel J. Berry
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Mark E. Morrey
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Roman Thaler
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Amel Dudakovic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew P. Abdel
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
12
|
Islam S, Sarkar O, Mukherjee S, Chattopadhyay A. Long-Term Impact of Cr(VI) Exposure in Swiss Albino Mice: ROS-Driven Modulation of Autophagy and Cellular Fate. Biol Trace Elem Res 2025:10.1007/s12011-025-04599-w. [PMID: 40180680 DOI: 10.1007/s12011-025-04599-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Abstract
Hexavalent chromium [Cr(VI)], due to its high solubility and permeability, is significantly more toxic than trivalent chromium [Cr(III)] as it generates reactive oxygen species (ROS) during cellular reduction. Industrial discharges have led to increasing Cr(VI) contamination in surface and groundwater, posing serious environmental and public health concerns. In our previous study, we demonstrated that exposure to 5 ppm Cr(VI) for 4 and 8 months adversely affected body weight, water consumption, and liver function in Swiss albino mice. Histological analyses revealed tissue alterations, disrupted DNA repair gene expression in liver tissue, and a marked increase in apoptotic gene expression after 8 months of exposure. Building on these findings, we employed the same Cr(VI) concentration (5 ppm via drinking water) over 4 and 8 months in the present study. Our results showed a significant increase in ROS generation in the liver, brain, and kidney tissues at both time intervals. Additionally, the presence of autophagolysosomes was markedly elevated after chronic Cr(VI) exposure in each tissue. We also observed altered expression patterns of key autophagy-related genes (Atg5, Beclin1, and Lc3) and mTor in these tissues. Immunohistochemical analysis further confirmed a significant increase in LC3B expression after 4 months of exposure. Our findings suggest that heightened intracellular oxidative stress triggers a protective autophagy response, mediated via mTOR signaling, to maintain cellular integrity. However, prolonged toxic insult and ROS accumulation may eventually shift pro-survival autophagy toward apoptotic cell death in the liver and brain tissues.
Collapse
Affiliation(s)
- Shehnaz Islam
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | - Olivia Sarkar
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | - Sunanda Mukherjee
- Department of Zoology, Visva-Bharati, Santiniketan, 731235, West Bengal, India
| | | |
Collapse
|
13
|
Goyal A, Chopra V, Garg K, Sharma S. Mechanisms coupling the mTOR pathway to chronic obstructive pulmonary disease (COPD) pathogenesis. Cytokine Growth Factor Rev 2025; 82:55-69. [PMID: 39799015 DOI: 10.1016/j.cytogfr.2024.12.005] [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: 10/18/2024] [Revised: 12/10/2024] [Accepted: 12/26/2024] [Indexed: 01/15/2025]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a poorly reversible respiratory disorder distinguished by dyspnea, cough, expectoration and exacerbations due to abnormality of airways or emphysema. In this review, we consider the therapeutic potential of targeting Mammalian target of Rapamycin (mTOR) for treating COPD. The mTOR is a highly conserved serine-threonine protein kinase that integrates signals from growth factors and nutrients to control protein synthesis, lipid biogenesis and metabolism. Dysregulated mTOR pathway signaling due to genetic factors or cigarette smoking impairs autophagy, driving the buildup of abnormal cells and damaged proteins, resulting in inflammation and oxidative stress. Persistent mTOR activation also contributes to pulmonary vascular cell proliferation, facilitating the development of pulmonary resistance in COPD. Rapamycin, an inhibitor of mTOR, prevents the buildup of senescent cells in the lungs of COPD patients and inhibits the release of lung tissue-damaging proteases. mTOR also impacts the corticosteroid sensitivity in COPD patients by regulating the levels of histone deacetylases. The emerging role of gut-lung axis dysbiosis in the progression of COPD and its influence on mTOR further highlights the relevance of the mTOR pathway in COPD pathophysiology.
Collapse
Affiliation(s)
- Ankita Goyal
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, India
| | - Vishal Chopra
- Department of Pulmonary Medicine, Government Medical College, Patiala, India
| | - Kranti Garg
- Department of Pulmonary Medicine, Government Medical College, Patiala, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, India.
| |
Collapse
|
14
|
Belmonte-Fernández A, Herrero-Ruíz J, Limón-Mortés MC, Sáez C, Japón MÁ, Mora-Santos M, Romero F. Overexpression of βTrCP1 elicits cell death in cisplatin-induced senescent cells. Cell Death Dis 2025; 16:203. [PMID: 40133262 PMCID: PMC11937513 DOI: 10.1038/s41419-025-07556-6] [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: 10/14/2024] [Revised: 02/22/2025] [Accepted: 03/17/2025] [Indexed: 03/27/2025]
Abstract
Senescence is a non-proliferative cellular state derived from aging or in response to exogenous insults, such as those that cause DNA damage. As a result of cancer treatments like cisplatin, certain tumor cells may undergo senescence. However, rather than being beneficial for patients, this is detrimental because these cells might proliferate again under specific conditions and, more importantly, because they synthesize and secrete molecules that promote the proliferation of nearby cells. Therefore, to achieve complete tumor remission, it is necessary to develop senolytic compounds to eliminate senescent cells. Here, we studied the role of βTrCP1 in cell proliferation and senescence and found that lentiviral overexpression of βTrCP1 induces the death of senescent cells obtained after cisplatin treatment in both two-dimensional cell cultures and tumorspheres. Mechanistically, we demonstrated that overexpression of βTrCP1 triggers proteasome-dependent degradation of p21 CIP1, allowing damaged cells to progress through the cell cycle and consequently die. Furthermore, we identified nucleophosmin 1 (NPM1) as the intermediary molecule involved in the effect of βTrCP1 on p21 CIP1. We determined that increased amounts of βTrCP1 partially retains NPM1 in the nucleoli, preventing it from associating with p21 CIP1, thus leaving it unprotected from degradation by the proteasome. These results have allowed us to discover a potential new target for senolytic drugs, as retaining NPM1 in the nucleoli under senescent conditions induces cell death.
Collapse
Affiliation(s)
| | - Joaquín Herrero-Ruíz
- Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain
| | | | - Carmen Sáez
- Instituto de Biomedicina de Sevilla (IBiS) and Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Miguel Á Japón
- Instituto de Biomedicina de Sevilla (IBiS) and Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Mar Mora-Santos
- Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain
| | - Francisco Romero
- Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
| |
Collapse
|
15
|
Du H, Mizokami A, Ni J, Zhang S, Yamawaki Y, Sano T, Jimi E, Tanida I, Kanematsu T. Role of Testosterone Signaling in Microglia: A Potential Role for Sex-Related Differences in Alzheimer's Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413375. [PMID: 40125707 DOI: 10.1002/advs.202413375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/28/2025] [Indexed: 03/25/2025]
Abstract
Alzheimer's disease (AD) is less prevalent in men than in women, although mechanisms remain unclear. Microglia degrade aggregated amyloid β (Aβ) through the lysosomal system, including autophagy. G protein-coupled receptor family C group 6 member A (GPRC6A), predominantly expressed in mouse microglial MG6 cells, is a primary mediator of testosterone signaling. This study examines testosterone's role in modulating Aβ-induced autophagy in microglia. Testosterone promotes Aβ-induced autophagy leading to Aβ clearance in MG6 cells by suppressing extracellular signal-regulated kinase (ERK) phosphorylation and subsequently inhibiting mammalian target of rapamycin (mTOR) activation, which is abrogated by shRNA knockdown of GPRC6A. In in vivo experiments with male 5xFAD AD model mice, Aβ clearance activity is associated with autophagy in microglia and is reduced by orchiectomy, but restored by testosterone supplementation. ERK phosphorylation in the brains of male AD model mice is upregulated by orchiectomy. Therefore, testosterone is involved in autophagy-mediated Aβ clearance in microglia. Aβ accumulation in human brain samples from patients with AD is significantly lower in men than in women, with less pronounced colocalization of Aβ with p62 aggregates, suggesting enhanced autophagic activity in men. In conclusion, testosterone enhances Aβ-induced autophagy in microglia, possibly contributing to lower susceptibility to AD in men.
Collapse
Affiliation(s)
- Haiyan Du
- Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Akiko Mizokami
- OBT Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Junjun Ni
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
| | - Simeng Zhang
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
| | - Yosuke Yamawaki
- Department of Advanced Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, 815-8511, Japan
| | - Tomomi Sano
- Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Eijiro Jimi
- OBT Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Laboratory of Molecular and Cellular Biochemistry, Division of Oral Biological Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Isei Tanida
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan
| | - Takashi Kanematsu
- Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| |
Collapse
|
16
|
Manganelli V, Costanzo M, Caissutti D, Salvatori I, Candelise N, Montalesi E, De Simone G, Ferri A, Garofalo T, Sorice M, Ruoppolo M, Longo A, Misasi R. Neuroglobin regulates autophagy through mTORC1/RAPTOR/ULK-1 pathway in human neuroblastoma cells. Sci Rep 2025; 15:7642. [PMID: 40038411 PMCID: PMC11880548 DOI: 10.1038/s41598-025-91701-w] [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: 11/27/2024] [Accepted: 02/21/2025] [Indexed: 03/06/2025] Open
Abstract
Neuroglobin (NGB) is a hexacoordinated hemeprotein mainly expressed in neurons. Following its upregulation and mitochondrial localization, NGB plays a pro-survival role against neuronal stress. Previously, we built a stable NGB-FLAG-overexpressing neuroblastoma cell line and showed that NGB promotes autophagy and localizes in autophagolysosomes. Here we studied the interactome of NGB-FLAG cells to identify novel autophagy-related NGB-binding partners and investigate how its upregulation could induce autophagy. LC3-II and p62 levels as well as mTORC1 activity were analyzed to evaluate autophagy in NGB-FLAG cells. NGB interactors were identified by affinity purification-mass spectrometry and protein-protein interaction network analysis and validated by immunoprecipitation. The increase of LC3-II and decrease of p62 in NGB-FLAG compared to control confirmed that NGB overexpression promotes autophagy. Interactome analysis identified the Regulatory associated protein of mTOR (RPTOR) as one of 134 putative NGB interactors, further validated by immunoprecipitation. NGB overexpression also determined a consistent increment of RPTOR phosphorylation at Ser792 which is required for mTORC1 inhibition, then confirmed by lower levels of phospho-mTOR and phospho-ULK1 in NGB-FLAG compared to control. Collectively, our data suggests that NGB is a positive regulator of autophagy. Through association with RPTOR, NGB may promote its activation and inhibit mTORC1 repressive activity on autophagy initiation.
Collapse
Affiliation(s)
- Valeria Manganelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Michele Costanzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, 80131, Italy
- CEINGE-Biotecnologie Avanzate Franco Salvatore S.C.Ar.L, Naples, 80145, Italy
| | - Daniela Caissutti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Illari Salvatori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
- Santa Lucia Foundation IRCCS, Rome, 00179, Italy
| | - Niccolò Candelise
- National Center for Drug Research and Evaluation, Italian National Institute of Health (ISS), Rome, 00161, Italy
| | - Emiliano Montalesi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Giovanna De Simone
- Department of Sciences, University of Rome "Roma Tre", Rome, 00146, Italy
| | - Alberto Ferri
- Santa Lucia Foundation IRCCS, Rome, 00179, Italy
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, 00133, Italy
| | - Tina Garofalo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Maurizio Sorice
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, 80131, Italy
- CEINGE-Biotecnologie Avanzate Franco Salvatore S.C.Ar.L, Naples, 80145, Italy
| | - Agostina Longo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy
| | - Roberta Misasi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy.
| |
Collapse
|
17
|
Li T, Huang N, Chen H, Yang Y, Zhang J, Xu W, Gong H, Gong C, Yang M, Zhao T, Wang F, Xiao H. Daytime-Restricted Feeding Alleviates D-Galactose-Induced Aging in Mice and Regulates the AMPK and mTORC1 Activities. J Cell Physiol 2025; 240:e70020. [PMID: 40070151 DOI: 10.1002/jcp.70020] [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: 09/01/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/17/2025]
Abstract
Time-restricted feeding (TRF) is a distinct regimen of intermittent fasting advocated for health improving. Although nighttime TRF (NRF) in rodents is analogous to daytime TRF (DRF) in humans and has health benefits, the effects of DRF on rodent's health remain uncertain. The adverse health effects of DRF in rodents are primarily attributed to its implementation-induced temporal shift in the expression of circadian rhythm-related genes. However, studies also demonstrate the health-beneficial effect of restricted feeding itself on metabolic homeostasis, particularly in periphery tissues. Moreover, the direct effects of DRF on aging progression in rodents are underexplored, highlighting a gap in current research. To explore the overall health effects of long-term DRF in rodents, especially its influence on aging progression, we investigated the impact of long-term DRF on mice under a progeric aging condition. Results showed that both 4-h and 8-h DRF regimens exerted positive effects on aging retardation; these effects were manifested as improved physical and memory capacities, enhanced liver and kidney functions, and reduced oxidative damage and inflammatory response. These DRF regimens also lowered the manifestation of aging-related markers in peripheral tissues, with decreased SA-β-gal staining and p16 expression. Mechanistically, DRF regimens, especially DRF8, upregulated AMPK signaling and downregulated mTORC1 signaling. Interestingly, the health benefits of DRF are similar to those of metformin intervention. In conclusion, our study demonstrates for the first time that DRF effectively counteracts oxidative stress-induced aging progression in mice, supporting the viewpoint that TRF as a promising strategy for preventing aging and aging-related disorders.
Collapse
Affiliation(s)
- Tiepeng Li
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ning Huang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China
| | - Honghan Chen
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Yang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Zhang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Weitong Xu
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Gong
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Chuhui Gong
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Yang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Zhao
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Fangfang Wang
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hengyi Xiao
- National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
18
|
Abo-Zaid OAR, Moawed FSM, Eldin ES, Farrag MA, Ahmed ESA. Antitumor activity of gamma-irradiated Rosa canina L. against lung carcinoma in rat model: a proposed mechanism. BMC Complement Med Ther 2025; 25:86. [PMID: 40022036 PMCID: PMC11869437 DOI: 10.1186/s12906-025-04813-1] [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: 08/20/2024] [Accepted: 02/05/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Lung cancer is one of the most prevalent malignancies globally and is the leading cause of cancer-related mortality. Although cisplatin is a widely utilized chemotherapeutic agent, its clinical efficacy is often hampered by significant toxicity and undesirable side effects. Rosa canina, a medicinal plant, has demonstrated a range of beneficial biological activities, including anti-inflammatory, anticancer, immunomodulatory, antioxidant, and genoprotective effects. METHODS This study aimed to investigate the potential of Rosa canina to enhance the anticancer efficacy of cisplatin in a dimethyl benz(a)anthracene-induced lung cancer model using female rats. The animals were administered Rosa canina, cisplatin, or a combination of both treatments. The expression levels of critical signaling molecules were evaluated, including phosphoinositide-3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), cleaved poly (ADP-ribose) polymerase (PARP-1), myeloid differentiation factor 88 (MyD88), and tumor necrosis factor receptor-associated factor (TRAF), in addition to various autophagic markers. Furthermore, we assessed the levels of toll-like receptor 2 (TLR2), nuclear factor kappa B (NF-κB), and apoptotic markers in lung tissue, complemented by histopathological examinations. RESULTS The combined treatment of Rosa canina extract and cisplatin significantly inhibited lung cancer cell proliferation by downregulating PARP-1 and the TLR2/MyD88/TRAF6/NF-κB signaling pathway, as well as the PI3K/Akt/mTOR pathway. Moreover, this combination therapy promoted autophagy and apoptosis, evidenced by elevated levels of autophagic and apoptotic markers. CONCLUSION Overall, the findings of this study suggest that Rosa canina enhances the anticancer effects of cisplatin by inhibiting cancer cell proliferation while simultaneously inducing autophagy and apoptosis. Thus, Rosa can be used as adjuvant to cisplatin chemotherapy to overcome its limitations which may be considered a new approach during lung cancer treatment strategy.
Collapse
Affiliation(s)
- Omayma A R Abo-Zaid
- Biochemistry and Molecular Biology Department, Faculty of Vet. Med, Benha University, Benha, Egypt
| | - Fatma S M Moawed
- Health Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Eman S Eldin
- Health Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Mostafa A Farrag
- Radiation Biology , National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Cairo, 11787, Egypt
| | - Esraa S A Ahmed
- Radiation Biology , National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Cairo, 11787, Egypt.
| |
Collapse
|
19
|
Gyurkovska V, Alvarado Cartagena YM, Murtazina R, Zhao SF, Ximenez de Olaso C, Segev N. Selective clearance of aberrant membrane proteins by TORC1-mediated micro-ER-phagy. Cell Rep 2025; 44:115282. [PMID: 39946230 PMCID: PMC11999474 DOI: 10.1016/j.celrep.2025.115282] [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: 05/31/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 02/28/2025] Open
Abstract
Aberrant accumulation and clearance of membrane proteins is associated with disease. Membrane proteins are inserted first to the endoplasmic reticulum (ER). During normal growth, two quality control (QC) processes, ER-associated degradation and macro-ER-phagy, deliver misfolded and excess membrane proteins for degradation in the proteasome and lysosome, respectively. We show that in yeast during normal growth, ER-QC is constitutive, since none of the stress-induced signaling pathways-nutritional, proteotoxic, or heat-are involved. In mutant cells defective in ER-QC, misfolded or excess proteins accumulate and nutritional stress, but not proteotoxic or heat stress, can stimulate their clearance. Early during nutritional stress, clearance occurs in the lysosome through a selective micro-ER-phagy pathway dependent on the ubiquitin ligase Rsp5, its Ssh4 adaptor, and ESCRT. In contrast, only a fraction of normal membrane proteins is degraded much later via macro-autophagy. Because the pathways explored here are conserved, nutritional stress emerges as a possible way for clearing disease-associated membrane proteins.
Collapse
Affiliation(s)
- Valeriya Gyurkovska
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Yaneris M Alvarado Cartagena
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Rakhilya Murtazina
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Sarah F Zhao
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Candela Ximenez de Olaso
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Nava Segev
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
| |
Collapse
|
20
|
Krawczyk A, Sladowska GE, Strzalka-Mrozik B. The Role of the Gut Microbiota in Modulating Signaling Pathways and Oxidative Stress in Glioma Therapies. Cancers (Basel) 2025; 17:719. [PMID: 40075568 PMCID: PMC11899293 DOI: 10.3390/cancers17050719] [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: 01/12/2025] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the gut microbiota is essential for maintaining CNS homeostasis, as it modulates immune responses, oxidative status, and neuroinflammation. The microbiota-gut-brain axis, a bidirectional communication network, plays a pivotal role in cancer and CNS disease treatment, exerting its influence through neural, endocrine, immunological, and metabolic pathways. Recent studies suggest that the gut microbiota influences the solidification of the tumor microenvironment and that dysbiosis may promote glioma development by modulating systemic inflammation and oxidative stress, which contributes to tumorigenesis and CNS tumor progression. This review interrogates the impact of the gut microbiota on glioma, focusing on critical pathways such as NF-κB, MAPK, PI3K/Akt/mTOR, and Kynurenine/AhR that drive tumor proliferation, immune evasion, and therapy resistance. Furthermore, we explore emerging therapeutic strategies, including probiotics and microbiota-based interventions, which show potential in modulating these pathways and enhancing immunotherapies such as checkpoint inhibitors. By focusing on the multifaceted interactions between the gut microbiota, oxidative stress, and CNS tumors, this review highlights the potential of microbiota-targeted therapies and their manipulation to complement and enhance current treatments.
Collapse
Affiliation(s)
| | | | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (A.K.); (G.E.S.)
| |
Collapse
|
21
|
Trisal A, Singh AK. Mechanisms and early efficacy data of caloric restriction and caloric restriction mimetics in neurodegenerative disease. Neuroscience 2025; 567:235-248. [PMID: 39761825 DOI: 10.1016/j.neuroscience.2025.01.004] [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: 07/22/2024] [Revised: 12/28/2024] [Accepted: 01/02/2025] [Indexed: 01/15/2025]
Abstract
Neurodegenerative disorders (NDDs) have been prevalent for more than a decade, and the number of individuals affected per year has increased exponentially. Among these NDDs, Alzheimer's disease, which causes extreme cognitive impairment, and Parkinson's disease, characterized by impairments in motor activity, are the most prevalent. While few treatments are available for clinical practice, they have minimal effects on reversing the neurodegeneration associated with these debilitating diseases. Lifestyle modifications and dietary choices are emerging and promising approaches to combat these disorders. Of the lifestyle changes that one could adopt, a major habit is caloric restriction. Caloric restriction (CR) is a lifestyle modification in which the amount of calories ingested is reduced to a significant amount without resulting in malnutrition. However, maintaining such a lifestyle is challenging. As alternatives, certain compounds have been recognized to mimic the effects produced by CR. These compounds are called caloric restriction mimetics (CRMs). Among these compounds, some have been designated established CRMs, namely, resveratrol, metformin, and rapamycin, whereas several other candidates are termed potential CRMs because of a lack of conclusive evidence of their effects. The potential CRMs discussed in this review are quercetin, chrysin, astragalin, apigenin, curcumin, epigallocatechin-3-gallate, and NAD+ precursors. This review aims to provide an overview of these CRMs' effectiveness in preventing neurodegenerative disorders associated with aging. Moreover, we highlight the clinical relevance of these compounds by discussing in detail the results of clinical trials on them.
Collapse
Affiliation(s)
- Anchal Trisal
- Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India; Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Abhishek Kumar Singh
- Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India; Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India.
| |
Collapse
|
22
|
Lin H, Xu Y, Xiong H, Wang L, Shi Y, Wang D, Wang Z, Ren J, Wang S. Mechanism of action of Panax ginseng alcohol extract based on orexin-mediated autophagy in the treatment of sleep and cognition in aged sleep-deprived rats. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118907. [PMID: 39389397 DOI: 10.1016/j.jep.2024.118907] [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: 08/13/2024] [Revised: 09/29/2024] [Accepted: 10/04/2024] [Indexed: 10/12/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panax ginseng (P. ginseng) C. A. Meyer. has been used extensively globally as a medicine. It has a therapeutic effect on sleep and is an attractive alternative for patients with insomnia. The United States Patent of Invention has approved the use of P. ginseng alcohol extract (GAE) in nutraceuticals or food to improve sleep. It has shown promise as an effective therapeutic agent for improving sleep and cognition. However, its mechanism of action is not yet fully understood. AIM OF THE STUDY To investigate the therapeutic benefits of GAE on sleep and cognition and its underlying mechanism in aged sleep-deprived rats, with a focus on orexin-mediated autophagy function. MATERIALS AND METHODS We conducted in vivo tests in an aged sleep-deprivation rat model produced using p-chlorophenylalanine (PCPA) coupled with modified multi-platform method to examine the therapeutic effects and mechanisms of GAE. A pentobarbital sodium-induced sleep test and water maze were used to assess sleep and cognitive performance, respectively. An enzyme-linked immunosorbent assay was used to determine orexin levels and aging and sleep markers in serum and hypothalamic tissues. Hematoxylin-eosin staining and Nissl staining were used to assess histopathological changes, and autophagy levels were assessed using transmission electron microscopy, immunofluorescence. Western blot and immunohistochemical staining were performed to detect the levels of orexin, orexin-receptor proteins, and autophagy-associated proteins to study the effects of GAE on hippocampal neurons, and the underlying mechanisms. RESULTS In aged sleep-deprived rats, GAE treatment prolonged sleep duration, improved cognitive function, prevented hippocampal neuronal damage, increased the number of Nissl bodies, improved aging and sleep markers, and enhanced the LC3A/B expression in autophagosomes and neurons. The amount of orexin in serum and hypothalamic tissue and OX1R, OX2R, and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) proteins also reduced, which resulted in the inhibition of the PI3K/Akt/mTOR pathway and activation of the autophagy process. CONCLUSIONS GAE may reduce hypothalamic orexin secretion and interact with orexin receptors to inhibit the PI3K/Akt/mTOR signalling network and activate autophagy. This may be a potential mechanism of action of GAE in regulating sleep-related cognitive function.
Collapse
Affiliation(s)
- Haining Lin
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Yunlong Xu
- Prevention and Treatment Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Huazhong Xiong
- Prevention and Treatment Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Lichao Wang
- Prevention and Treatment Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Yuqing Shi
- College of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Dongyi Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Zixu Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Jixiang Ren
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China.
| | - Siming Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun University of Chinese Medicine, Changchun, 130117, China.
| |
Collapse
|
23
|
Ghionescu AV, Uta M, Sorop A, Lazar C, Flintoaca-Alexandru PR, Chiritoiu G, Sima L, Petrescu SM, Dima SO, Branza-Nichita N. The endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients. J Biomed Sci 2025; 32:11. [PMID: 39838427 PMCID: PMC11752926 DOI: 10.1186/s12929-024-01103-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 11/17/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a major risk for development of hepatocellular carcinoma (HCC), a frequent malignancy with a poor survival rate. HBV infection results in significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling, a contributing factor to carcinogenesis. As part of the UPR, the ER-associated degradation (ERAD) pathway is responsible for removing the burden of misfolded secretory proteins, to re-establish cellular homeostasis. Emerging evidence indicates consistent upregulation of ERAD factors, including members of the ER degradation-enhancing alpha-mannosidase-like protein (EDEM) family in infection and various tumor types. However, the significance of this gene expression pattern in HBV-driven pathology is just beginning to be deciphered. METHODS In this study we quantified the expression of the ERAD factor EDEM3, in a cohort of HCC patients with and without HBV infection, and validated our results by analysis of publically available transcriptomic and microarray data sets. We performed mechanistic studies in HepaRG cells with modulated EDEM3 expression to address UPR, ERAD, autophagy and apoptosis signaling, and their consequences on HBV infection. RESULTS Our work revealed significantly elevated EDEM3 expression in HCC tissues irrespective of HBV infection, while the highest levels were observed in tissues from HBV-infected patients. Investigation of published transcriptomic data sets confirmed EDEM3 upregulation in independent HCC patient cohorts, associated with tumor progression, poor survival prognosis and resistance to therapy. EDEM3-overexpressing hepatic cells exhibited attenuated UPR and activated secretory autophagy, which promoted HBV production. Conversely, cell depletion of EDEM3 resulted in significant ER stress inducing pro-apoptotic mechanisms and cell death. CONCLUSIONS We provide evidence of major implications of the ERAD pathway in HBV infection and HCC development and progression. Our results suggest that ERAD activation in HBV-infected cells is a protective mechanism against prolonged ER stress, potentially contributing to establishment of chronic HBV infection and promoting tumorigenesis. Developing specific inhibitors for ERAD factors may be an attractive approach to improve efficiency of current antiviral and anticancer therapies.
Collapse
Affiliation(s)
- Alina-Veronica Ghionescu
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania
| | - Mihaela Uta
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania
| | - Catalin Lazar
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania
| | | | - Gabriela Chiritoiu
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Livia Sima
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Stefana-Maria Petrescu
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania.
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Soseaua Fundeni 258, Sector 2, 022328, Bucharest, Romania.
| | - Norica Branza-Nichita
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, Sector 6, 060031, Bucharest, Romania.
| |
Collapse
|
24
|
Mohan M, Mannan A, Nauriyal A, Singh TG. Emerging targets in amyotrophic lateral sclerosis (ALS): The promise of ATP-binding cassette (ABC) transporter modulation. Behav Brain Res 2025; 476:115242. [PMID: 39243983 DOI: 10.1016/j.bbr.2024.115242] [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: 08/13/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.
Collapse
Affiliation(s)
- Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Aayush Nauriyal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| |
Collapse
|
25
|
Liu Q, Sun Y, He B, Chen H, Wang L, Wang G, Zhang K, Zhao X, Zhang X, Shen D, Zhang X, Cui L. Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment. Acta Neuropathol Commun 2025; 13:2. [PMID: 39755715 DOI: 10.1186/s40478-024-01919-4] [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: 08/27/2024] [Accepted: 12/20/2024] [Indexed: 01/06/2025] Open
Abstract
Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction.
Collapse
Affiliation(s)
- Qing Liu
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China.
| | - Ye Sun
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China
| | - Baodong He
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China
| | - Haodong Chen
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China
| | - Lijing Wang
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China
| | - Gaojie Wang
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China
| | - Kang Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Ximeng Zhao
- State Key Laboratory of Medical Molecular Biology, Mckusick-Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences, PUMC and CAMS, Beijing, China
| | - Xinzhe Zhang
- State Key Laboratory of Medical Molecular Biology, Mckusick-Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences, PUMC and CAMS, Beijing, China
| | - Dongchao Shen
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China
| | - Xue Zhang
- State Key Laboratory of Medical Molecular Biology, Mckusick-Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences, PUMC and CAMS, Beijing, China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, PUMCH, Beijing, China.
| | - Liying Cui
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College (PUMC) and Chinese Academy of Medical Science (CAMS), Beijing, China.
| |
Collapse
|
26
|
Liu TW, Tian C, Li YX, Wang JX, Zhao XF. The steroid hormone 20-hydroxyecdysone inhibits RAPTOR expression by repressing Hox gene transcription to induce autophagy. J Biol Chem 2025; 301:108093. [PMID: 39706274 PMCID: PMC11786772 DOI: 10.1016/j.jbc.2024.108093] [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: 08/22/2024] [Revised: 11/11/2024] [Accepted: 12/07/2024] [Indexed: 12/23/2024] Open
Abstract
Regulatory-associated protein of TOR (RAPTOR) is a key component of TOR complex 1, which determines the lysosomal location and substrate recruitment of TOR complex 1 to promote cell growth and prevent autophagy. Many studies in recent decades have focused on the post-translational modification of RAPTOR; however, little is known about the transcriptional regulatory mechanism of Raptor. Using the lepidopteran insect cotton bollworm (Helicoverpa armigera) as model, we reveal the transcriptional regulatory mechanism of Raptor. RAPTOR has different expression profiles in tissues during development from larva to late pupa, with high expression levels at larval feeding stages but low expression levels during metamorphic stages in the epidermis, midgut, and fat body. RAPTOR is localized in the larval midgut at the feeding stage but is localized in the imaginal midgut at metamorphic stages. The knockdown of Raptor at the feeding stage results in the production of small pupae, early autophagy of the midgut and fat body, and decreased cell proliferation. However, Raptor knockdown at metamorphic stage represses the development of the epidermis, adult fat body, and brain. 20-Hydroxecdysone (20E) represses Raptor transcription. Homeobox (HOX) proteins promote Raptor transcription by binding to its promoter. Overexpression of HOX proteins represses autophagy-related gene expression and autophagy but increases cell proliferation. 20E represses Hox genes transcription via its nuclear receptor EcR binding to its promoters. Together, these findings suggest that HOX proteins are positive regulators that upregulate Raptor transcription. 20E represses Hox gene transcription, thus repressing Raptor expression, resulting in autophagy and repressing cell proliferation during metamorphosis.
Collapse
Affiliation(s)
- Tian-Wen Liu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Can Tian
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Yan-Xue Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Jin-Xing Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China.
| | - Xiao-Fan Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China.
| |
Collapse
|
27
|
Sugimoto Y, Takasaki T, Yamada R, Kurosaki R, Yamane T, Sugiura R. Rapamycin Abrogates Aggregation of Human α-Synuclein Expressed in Fission Yeast via an Autophagy-Independent Mechanism. Genes Cells 2025; 30:e13185. [PMID: 39695344 DOI: 10.1111/gtc.13185] [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: 09/09/2024] [Revised: 11/16/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Aggregation of alpha-synuclein (α-Syn) is implicated in the pathogenesis of several neurodegenerative disorders, such as Parkinson's disease and Dementia with Lewy bodies, collectively termed synucleinopathies. Thus, tremendous efforts are being made to develop strategies to prevent or inhibit α-Syn aggregation. Here, we genetically engineered fission yeast to express human α-Syn C-terminally fused to green fluorescent protein (GFP) at low and high levels. α-Syn was localized at the cell tips and septa at low-level expression. At high-level expression, α-Syn was observed to form cytoplasmic aggregates. Notably, rapamycin, a natural product that allosterically inhibits the mammalian target of rapamycin (mTOR) by forming a complex with FKBP12, and Torin1, a synthetic mTOR inhibitor that blocks ATP binding to mTOR, markedly reduced the number of cells harboring α-Syn aggregates. These mTOR inhibitors abrogate α-Syn aggregation without affecting α-Syn expression levels. Rapamycin, but not Torin1, failed to reduce α-Syn aggregation in the deletion cells of fkh1+, encoding FKBP12, indicating the requirement of FKBP12 for rapamycin-mediated inhibition of α-Syn aggregation. Importantly, the effect of rapamycin was also observed in the cells lacking atg1+, a key regulator of autophagy. Collectively, rapamycin abrogates human α-Syn aggregation expressed in fission yeast via an autophagy-independent mechanism mediated by FKBP12.
Collapse
Affiliation(s)
- Yoshitaka Sugimoto
- Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University, Higashiosaka, Japan
| | - Teruaki Takasaki
- Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University, Higashiosaka, Japan
| | - Ryuga Yamada
- Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University, Higashiosaka, Japan
| | - Ryo Kurosaki
- Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University, Higashiosaka, Japan
| | - Tomonari Yamane
- Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University, Higashiosaka, Japan
| | - Reiko Sugiura
- Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University, Higashiosaka, Japan
| |
Collapse
|
28
|
Lee CM, Lee HY, Jarrell ZR, Smith MR, Jones DP, Go YM. Mechanistic role for mTORC1 signaling in profibrotic toxicity of low-dose cadmium. Toxicol Appl Pharmacol 2025; 494:117159. [PMID: 39557346 DOI: 10.1016/j.taap.2024.117159] [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: 08/23/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Cadmium (Cd) is a toxic environmental metal that occurs naturally in food and drinking water. Cd is of increasing concern to human health due to its association with age-related diseases and long biological half-life. Previous studies show that low-dose Cd exposure via drinking water induces mechanistic target of rapamycin complex 1 (mTORC1) signaling in mice; however, the role of mTORC1 pathway in Cd-induced pro-fibrotic responses has not been established. In the present study, we used human lung fibroblasts to examine whether inhibiting the mTORC1 pathway prevents lung fibrosis signaling induced by low-dose Cd exposure. Results show that rapamycin, a pharmacological inhibitor of mTORC1, inhibited Cd-dependent phosphorylation of ribosomal protein S6, a downstream marker of mTORC1 activation. Rapamycin also decreased Cd-dependent increases in pro-fibrotic markers, α-smooth muscle actin, collagen 1α1 and fibronectin. Cd activated mitochondrial spare respiratory capacity in association with increased cell proliferation. Rapamycin decreased these responses, showing that mTORC1 signaling supports mitochondrial energy supply for cell proliferation, an important step in fibroblast trans-differentiation into myofibroblasts. Collectively, these results establish a key mechanistic role for mTORC1 activation in environmental Cd-dependent lung fibrosis.
Collapse
Affiliation(s)
- Choon-Myung Lee
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, United States of America
| | - Ho Young Lee
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, United States of America
| | - Zachery R Jarrell
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, United States of America
| | - M Ryan Smith
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, United States of America; VA Healthcare System of Atlanta, Decatur, GA 30033, USA
| | - Dean P Jones
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, United States of America.
| | - Young-Mi Go
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, United States of America.
| |
Collapse
|
29
|
Yu Z, Lin S, Gong X, Zou Z, Yang X, Ruan Y, Qian L, Liu Y, Si Z. The role of macroautophagy in substance use disorders. Ann N Y Acad Sci 2025; 1543:68-78. [PMID: 39714908 DOI: 10.1111/nyas.15272] [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] [Indexed: 12/24/2024]
Abstract
Macroautophagy, a universal cellular process, sends cellular material to lysosomes for breakdown and is often activated by stressors like hypoxia or drug exposure. It is vital for protein balance, neurotransmitter release, synaptic function, and neuron survival. The role of macroautophagy in substance use disorders is dual. On one hand, substances like cocaine, methamphetamine, opiates, and alcohol can activate macroautophagy pathways to degrade various neuroinflammatory factors in neuronal cells, providing a protective function. On the other hand, long-term and excessive use of addictive substances can inhibit macroautophagy pathways, obstructing the fusion of autophagosomes with lysosomes and losing the original protective function. This review first summarizes the key proteins and signaling pathways involved in macroautophagy, including mTORC1, AMPK, and endoplasmic reticulum stress, and suggests that the regulation of macroautophagy plays a central role in drug-rewarding behavior and addiction. Second, we focus on the interactions between macroautophagy and neuroinflammation induced by drugs, evaluating the potential of macroautophagy modulators as therapeutic strategies for substance use disorder (SUD), and identifying autophagy-related biomarkers that can be used for early diagnosis and monitoring of treatment response. Our review summarizes the important scientific basis involved in macroautophagy pathways for the development of new therapies for SUD.
Collapse
Affiliation(s)
- Zhaoying Yu
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Shujun Lin
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Xinshuang Gong
- Department of Medicine, School of Public Health, Ningbo University, Ningbo, China
| | - Zhiting Zou
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Xiangdong Yang
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Yuer Ruan
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Liyin Qian
- Department of Medicine, School of Public Health, Ningbo University, Ningbo, China
| | - Yu Liu
- Department of Medicine, School of Basic Medicine, Ningbo University, Ningbo, China
| | - Zizhen Si
- Department of Medicine, School of Basic Medicine, Ningbo University, Ningbo, China
| |
Collapse
|
30
|
Bae HR, Shin SK, Lee JY, Ko YJ, Kim S, Young HA, Kwon EY. Chronic Low-Level IFN-γ Expression Disrupts Mitochondrial Complex I Activity in Renal Macrophages: An Early Mechanistic Driver of Lupus Nephritis Pathogenesis. Int J Mol Sci 2024; 26:63. [PMID: 39795922 PMCID: PMC11720139 DOI: 10.3390/ijms26010063] [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: 11/09/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Mitochondrial dysfunction and macrophage dysregulation are well recognized as significant contributors to the pathogenesis of autoimmune diseases. However, the detailed mechanisms connecting these two factors remain poorly understood. This study hypothesizes that low but chronic interferon-gamma (IFN-γ) plays a critical role in these processes. To explore this, we utilized ARE-Del mice, a model characterized by sustained low-level IFN-γ expression and lupus nephritis (LN)-like symptoms. Age- and tissue-dependent gene expression analyses in ARE-Del mice revealed significant suppression of mitochondrial complex I components and activities, particularly in the kidneys. The genotype-dependent suppression of mitochondrial complex I indicates early disruption, which leads to macrophage dysfunction. Notably, remission restored gene expression of mitochondrial complex I and macrophage dysfunction in isolated renal macrophages from NZB/W lupus-prone mice. These findings suggest that chronic low-level IFN-γ disrupts mitochondrial complex I activity in macrophages, highlighting its role in the early pathogenesis of autoimmune diseases like lupus nephritis. This provides new insights into the molecular interactions underlying autoimmune pathogenesis and suggests potential targets for therapeutic intervention.
Collapse
Affiliation(s)
- Heekyong R. Bae
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea; (H.R.B.)
- Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Su-Kyung Shin
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea; (H.R.B.)
- Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Ji-Yoon Lee
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea; (H.R.B.)
- Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Yeo Jin Ko
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea; (H.R.B.)
- Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Suntae Kim
- Omixplus, LLC., Gaithersburg, MA 20850, USA
| | - Howard A. Young
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MA 21702, USA
| | - Eun-Young Kwon
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea; (H.R.B.)
- Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea
- Center for Beautiful Aging, Kyungpook National University, Daegu 41566, Republic of Korea
| |
Collapse
|
31
|
Chuang YC, Ou JHJ. Hepatitis B virus entry, assembly, and egress. Microbiol Mol Biol Rev 2024; 88:e0001424. [PMID: 39440957 DOI: 10.1128/mmbr.00014-24] [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] [Indexed: 10/25/2024] Open
Abstract
SUMMARYHepatitis B virus (HBV) is an important human pathogen that chronically infects approximately 250 million people in the world, resulting in ~1 million deaths annually. This virus is a hepatotropic virus and can cause severe liver diseases including cirrhosis and hepatocellular carcinoma. The entry of HBV into hepatocytes is initiated by the interaction of its envelope proteins with its receptors. This is followed by the delivery of the viral nucleocapsid to the nucleus for the release of its genomic DNA and the transcription of viral RNAs. The assembly of the viral capsid particles may then take place in the nucleus or the cytoplasm and may involve cellular membranes. This is followed by the egress of the virus from infected cells. In recent years, significant research progresses had been made toward understanding the entry, the assembly, and the egress of HBV particles. In this review, we discuss the molecular pathways of these processes and compare them with those used by hepatitis delta virus and hepatitis C virus , two other hepatotropic viruses that are also enveloped. The understanding of these processes will help us to understand how HBV replicates and causes diseases, which will help to improve the treatments for HBV patients.
Collapse
Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - J-H James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| |
Collapse
|
32
|
Paoletti I, Coccurello R. Irisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology. Int J Mol Sci 2024; 25:13480. [PMID: 39769243 PMCID: PMC11676223 DOI: 10.3390/ijms252413480] [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: 11/27/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/03/2025] Open
Abstract
The fibronectin domain-containing protein 5 (FNDC5), or irisin, is an adipo-myokine hormone produced during exercise, which shows therapeutic potential for conditions like metabolic disorders, osteoporosis, sarcopenia, obesity, type 2 diabetes, and neurodegenerative diseases, including Alzheimer's disease (AD). This review explores its potential across various pathophysiological processes that are often considered independent. Elevated in healthy states but reduced in diseases, irisin improves muscle-adipose communication, insulin sensitivity, and metabolic balance by enhancing mitochondrial function and reducing oxidative stress. It promotes osteogenesis and mitigates bone loss in osteoporosis and sarcopenia. Irisin exhibits anti-inflammatory effects by inhibiting NF-κB signaling and countering insulin resistance. In the brain, it reduces amyloid-β toxicity, inflammation, and oxidative stress, enhancing brain-derived neurotrophic factor (BDNF) signaling, which improves cognition and synaptic health in AD models. It also regulates dopamine pathways, potentially alleviating neuropsychiatric symptoms like depression and apathy. By linking physical activity to systemic health, irisin emphasizes its role in the muscle-bone-brain axis. Its multifaceted benefits highlight its potential as a therapeutic target for AD and related disorders, with applications in prevention, in treatment, and as a complement to exercise strategies.
Collapse
Affiliation(s)
- Ilaria Paoletti
- IRCSS Santa Lucia Foundation, European Center for Brain Research, 00143 Rome, Italy;
| | - Roberto Coccurello
- IRCSS Santa Lucia Foundation, European Center for Brain Research, 00143 Rome, Italy;
- Institute for Complex Systems (ISC), National Research Council (C.N.R.), 00185 Rome, Italy
| |
Collapse
|
33
|
Galhuber M, Thedieck K. ODE-based models of signaling networks in autophagy. CURRENT OPINION IN SYSTEMS BIOLOGY 2024; 39:100519. [DOI: 10.1016/j.coisb.2024.100519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
34
|
Millar MW, Najar RA, Slavin SA, Shadab M, Tahir I, Mahamed Z, Lin X, Abe JI, Wright TW, Dean DA, Fazal F, Rahman A. MTOR maintains endothelial cell integrity to limit lung vascular injury. J Biol Chem 2024; 300:107952. [PMID: 39510184 PMCID: PMC11664419 DOI: 10.1016/j.jbc.2024.107952] [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: 02/12/2024] [Revised: 09/21/2024] [Accepted: 10/09/2024] [Indexed: 11/15/2024] Open
Abstract
The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify mechanistic target of rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis of cell surface vascular endothelial (VE)-cadherin leading to disrupted barrier function. MTOR-depleted EC also exhibited reduced VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR2) levels mediated in part by autophagy. Similarly, lungs from mice with EC-specific MTOR deficiency displayed spontaneous vascular leakage marked by decreased VE-cadherin and VEGFR2 levels, indicating that MTOR deficiency in EC is sufficient to disrupt lung vascular integrity and may be a key pathogenic mechanism of ALI. Indeed, MTOR as well as VEGFR2 and VE-cadherin levels were markedly reduced in injured mouse lungs or EC. Importantly, EC-targeted gene transfer of MTOR complementary DNA, either prophylactically or therapeutically, mitigated inflammatory lung injury, and improved lung function and survival in mouse models of ALI. These findings reveal an essential role of MTOR in maintaining EC function, identify loss of endothelial MTOR as a key mechanism of lung vascular injury, and show the therapeutic potential of EC-targeted MTOR expression in combating ALI and mortality in mice.
Collapse
Affiliation(s)
- Michelle Warren Millar
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Rauf A Najar
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Spencer A Slavin
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Mohammad Shadab
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Imran Tahir
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Zahra Mahamed
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Xin Lin
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Jun-Ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Terry W Wright
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - David A Dean
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Fabeha Fazal
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Arshad Rahman
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
| |
Collapse
|
35
|
Rojas-Salazar Y, Gómez-Montañez E, Rojas-Salazar J, de Anda-Jáuregui G, Hernández-Lemus E. Potential Drug Synergy Through the ERBB2 Pathway in HER2+ Breast Tumors. Int J Mol Sci 2024; 25:12840. [PMID: 39684551 DOI: 10.3390/ijms252312840] [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: 10/23/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
HER2-positive (HER2+) breast cancer is characterized by the overexpression of the ERBB2 (HER2) gene, which promotes aggressive tumor growth and poor prognosis. Targeting the ERBB2 pathway with single-agent therapies has shown limited efficacy due to resistance mechanisms and the complexity of gene interactions within the tumor microenvironment. This study aims to explore potential drug synergies by analyzing gene-drug interactions and combination therapies that target the ERBB2 pathway in HER2+ breast tumors. Using gene co-expression network analysis, we identified 23 metabolic pathways with significant cross-linking of gene interactions, including those involving EGFR tyrosine kinase inhibitors, PI3K, mTOR, and others. We visualized these interactions using Cytoscape to generate individual and combined drug-gene networks, focusing on frequently used drugs such as Erlotinib, Gefitinib, Lapatinib, and Cetuximab. Individual networks highlighted the direct effects of these drugs on their target genes and neighboring genes within the ERBB2 pathway. Combined drug networks, such as those for Cetuximab with Lapatinib, Cetuximab with Erlotinib, and Erlotinib with Lapatinib, revealed potential synergies that could enhance therapeutic efficacy by simultaneously influencing multiple genes and pathways. Our findings suggest that a network-based approach to analyzing drug combinations provides valuable insights into the molecular mechanisms of HER2+ breast cancer and offers promising strategies for overcoming drug resistance and improving treatment outcomes.
Collapse
Affiliation(s)
- Yareli Rojas-Salazar
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Emiliano Gómez-Montañez
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Jorge Rojas-Salazar
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City 14610, Mexico
| | - Guillermo de Anda-Jáuregui
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City 14610, Mexico
- Center for Complexity Sciences, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Investigadores e Investigadoras por Mexico Program, Conahcyt, Mexico City 03940, Mexico
| | - Enrique Hernández-Lemus
- Computational Genomics Division, National Institute of Genomic Medicine, Mexico City 14610, Mexico
- Center for Complexity Sciences, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| |
Collapse
|
36
|
Smiles WJ, Ovens AJ, Kemp BE, Galic S, Petersen J, Oakhill JS. New developments in AMPK and mTORC1 cross-talk. Essays Biochem 2024; 68:321-336. [PMID: 38994736 PMCID: PMC12055038 DOI: 10.1042/ebc20240007] [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: 05/09/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/13/2024]
Abstract
Metabolic homeostasis and the ability to link energy supply to demand are essential requirements for all living cells to grow and proliferate. Key to metabolic homeostasis in all eukaryotes are AMPK and mTORC1, two kinases that sense nutrient levels and function as counteracting regulators of catabolism (AMPK) and anabolism (mTORC1) to control cell survival, growth and proliferation. Discoveries beginning in the early 2000s revealed that AMPK and mTORC1 communicate, or cross-talk, through direct and indirect phosphorylation events to regulate the activities of each other and their shared protein substrate ULK1, the master initiator of autophagy, thereby allowing cellular metabolism to rapidly adapt to energy and nutritional state. More recent reports describe divergent mechanisms of AMPK/mTORC1 cross-talk and the elaborate means by which AMPK and mTORC1 are activated at the lysosome. Here, we provide a comprehensive overview of current understanding in this exciting area and comment on new evidence showing mTORC1 feedback extends to the level of the AMPK isoform, which is particularly pertinent for some cancers where specific AMPK isoforms are implicated in disease pathogenesis.
Collapse
Affiliation(s)
- William J Smiles
- Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Ashley J Ovens
- Protein Engineering in Immunity and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia
| | - Bruce E Kemp
- Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
- Mary Mackillop Institute for Health Research, Australian Catholic University, Fitzroy, Vic 3065, Vic. Australia
| | - Sandra Galic
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
- Metabolic Physiology, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA 5042, Australia
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Jonathan S Oakhill
- Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
| |
Collapse
|
37
|
Azimzadeh M, Cheah PS, Ling KH. Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target. Biochem Biophys Res Commun 2024; 733:150713. [PMID: 39307112 DOI: 10.1016/j.bbrc.2024.150713] [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: 05/12/2024] [Revised: 08/27/2024] [Accepted: 09/16/2024] [Indexed: 10/06/2024]
Abstract
Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life.
Collapse
Affiliation(s)
- Mansour Azimzadeh
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Pike-See Cheah
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Malaysian Research Institute on Ageing (MyAgeing®), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
| | - King-Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Malaysian Research Institute on Ageing (MyAgeing®), Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
| |
Collapse
|
38
|
Chu L, Liu A, Chang J, Zhang J, Hou X, Zhu X, Xing Q, Bao Z. TORC1 Regulates Thermotolerance via Modulating Metabolic Rate and Antioxidant Capacity in Scallop Argopecten irradians irradians. Antioxidants (Basel) 2024; 13:1359. [PMID: 39594501 PMCID: PMC11591371 DOI: 10.3390/antiox13111359] [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: 08/25/2024] [Revised: 11/03/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Target of rapamycin complex 1 (TORC1) is a key regulator of metabolism in eukaryotes across multiple pathways. Although TORC1 has been extensively studied in vertebrates and some invertebrates, research on this complex in scallops is limited. In this study, we identified the genes encoding TORC1 complex subunits in the scallop Argopecten irradians irradians through genome-wide in silico scanning. Five genes, including TOR, RAPTOR, LST8, DEPTOR, and PRAS40, that encode the subunits of TORC1 complex were identified in the bay scallop. We then conducted structural characterization and phylogenetic analysis of the A. i. irradians TORC1 (AiTORC1) subunits to determine their structural features and evolutionary relationships. Next, we analyzed the spatiotemporal expressions of AiTORC1-coding genes during various embryo/larvae developmental stages and across different tissues in healthy adult scallops. The results revealed stage- and tissue-specific expression patterns, suggesting diverse roles in development and growth. Furthermore, the regulation of AiTORC1-coding genes was examined in temperature-sensitive tissues (the mantle, gill, hemocyte, and heart) of bay scallops exposed to high-temperature (32 °C) stress over different durations (0 h, 6 h, 12 h, 24 h, 3 d, 6 d, and 10 d). The expression of AiTORC1-coding genes was predominantly suppressed in the hemocyte but was generally activated in the mantle, gill, and heart, indicating a tissue-specific response to heat stress. Finally, functional validation was performed using the TOR inhibitor rapamycin to suppress AiTORC1, leading to an enhanced catabolism, a decreased antioxidant capacity, and a significant reduction in thermotolerance in bay scallops. Collectively, this study elucidates the presence, structural features, evolutional relationships, expression profiles, and roles in antioxidant capacity and metabolism regulation of AiTORC1 in the bay scallop, providing a preliminary understanding of its versatile functions in response to high-temperature challenges in marine mollusks.
Collapse
Affiliation(s)
- Longfei Chu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
| | - Ancheng Liu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
| | - Jiaxi Chang
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
| | - Junhao Zhang
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
| | - Xiujiang Hou
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
| | - Xinghai Zhu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
| | - Qiang Xing
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao 266237, China
| | - Zhenmin Bao
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; (L.C.); (A.L.); (J.C.); (J.Z.); (X.H.); (X.Z.); (Z.B.)
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao 266237, China
| |
Collapse
|
39
|
Mandic M, Paunovic V, Vucicevic L, Kosic M, Mijatovic S, Trajkovic V, Harhaji-Trajkovic L. No energy, no autophagy-Mechanisms and therapeutic implications of autophagic response energy requirements. J Cell Physiol 2024; 239:e31366. [PMID: 38958520 DOI: 10.1002/jcp.31366] [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: 02/01/2024] [Revised: 05/29/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024]
Abstract
Autophagy is a lysosome-mediated self-degradation process of central importance for cellular quality control. It also provides macromolecule building blocks and substrates for energy metabolism during nutrient or energy deficiency, which are the main stimuli for autophagy induction. However, like most biological processes, autophagy itself requires ATP, and there is an energy threshold for its initiation and execution. We here present the first comprehensive review of this often-overlooked aspect of autophagy research. The studies in which ATP deficiency suppressed autophagy in vitro and in vivo were classified according to the energy pathway involved (oxidative phosphorylation or glycolysis). A mechanistic insight was provided by pinpointing the critical ATP-consuming autophagic events, including transcription/translation/interaction of autophagy-related molecules, autophagosome formation/elongation, autophagosome fusion with the lysosome, and lysosome acidification. The significance of energy-dependent fine-tuning of autophagic response for preserving the cell homeostasis, and potential implications for the therapy of cancer, autoimmunity, metabolic disorders, and neurodegeneration are discussed.
Collapse
Affiliation(s)
- Milos Mandic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Verica Paunovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ljubica Vucicevic
- Department of Neurophysiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Milica Kosic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Srdjan Mijatovic
- Clinic for Emergency Surgery, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Vladimir Trajkovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ljubica Harhaji-Trajkovic
- Department of Neurophysiology, Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
40
|
Chen M, Wang X, Bao S, Wang D, Zhao J, Wang Q, Liu C, Zhao H, Zhang C. Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease. Int J Biol Macromol 2024; 281:136119. [PMID: 39343259 DOI: 10.1016/j.ijbiomac.2024.136119] [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: 06/22/2024] [Revised: 08/24/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Apitherapy has a long history in treating Parkinson's disease (PD) in humans, with evidence suggesting that bee venom (BV) can mitigate Parkinson's symptoms. Central to BV's effects is melittin (MLT), a principal peptide whose neuroprotective mechanisms in PD are not fully understood. The study investigated the effects of MLT on an experimental PD model in mice and dopaminergic neuron cells, induced by MPTP or MPP+. We concentrate on the autophagic response elicited by MLT during PD pathogenesis. The findings showed that MLT was shown to protect against MPP+/MPTP cytotoxicity and preserve tyrosine hydroxylase (TH) levels, indicating neuronal safeguarding. Remarkably, MLT instigated mitophagy, enhancing mitochondrial homeostasis in MPP+-exposed SH-SY5Y cells. Further, MLT's promotion of mitophagy was confirmed to be AMPK/mTOR signaling-dependent. Validation using Bafilomycin A1, an autophagy inhibitor, confirmed MLT's neuroprotective role, with autophagy inhibition negating MLT's benefits and reducing TH preservation. These findings illuminate MLT's therapeutic potential, particularly its modulation of mitochondrial dysfunction in PD pathology. Our research advances the understanding of MLT's mechanistic action, emphasizing its role in mitochondrial autophagy and AMPK/mTOR signaling, offering a novel perspective beyond the symptomatic relief associated with BV.
Collapse
Affiliation(s)
- Mingran Chen
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Xue Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Shuangyan Bao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Dexiao Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Jie Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Qian Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Chaojie Liu
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Haiong Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
| |
Collapse
|
41
|
Jarocki M, Turek K, Saczko J, Tarek M, Kulbacka J. Lipids associated with autophagy: mechanisms and therapeutic targets. Cell Death Discov 2024; 10:460. [PMID: 39477959 PMCID: PMC11525783 DOI: 10.1038/s41420-024-02224-8] [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: 04/24/2024] [Revised: 10/18/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.
Collapse
Affiliation(s)
- Michał Jarocki
- University Clinical Hospital, Wroclaw Medical University, Wroclaw, Poland
| | | | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Mounir Tarek
- Université de Lorraine, CNRS, LPCT, Nancy, France
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland.
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
| |
Collapse
|
42
|
Malik JA, Zafar MA, Singh S, Nanda S, Bashir H, Das DK, Lamba T, Khan MA, Kaur G, Agrewala JN. From defense to dysfunction: Autophagy's dual role in disease pathophysiology. Eur J Pharmacol 2024; 981:176856. [PMID: 39068979 DOI: 10.1016/j.ejphar.2024.176856] [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: 06/15/2024] [Revised: 07/16/2024] [Accepted: 07/24/2024] [Indexed: 07/30/2024]
Abstract
Autophagy is a fundamental pillar of cellular resilience, indispensable for maintaining cellular health and vitality. It coordinates the meticulous breakdown of cytoplasmic macromolecules as a guardian of cell metabolism, genomic integrity, and survival. In the complex play of biological warfare, autophagy emerges as a firm defender, bravely confronting various pathogenic, infectious, and cancerous adversaries. Nevertheless, its role transcends mere defense, wielding both protective and harmful effects in the complex landscape of disease pathogenesis. From the onslaught of infectious outbreaks to the devious progression of chronic lifestyle disorders, autophagy emerges as a central protagonist, convolutedly shaping the trajectory of cellular health and disease progression. In this article, we embark on a journey into the complicated web of molecular and immunological mechanisms that govern autophagy's profound influence over disease. Our focus sharpens on dissecting the impact of various autophagy-associated proteins on the kaleidoscope of immune responses, spanning the spectrum from infectious outbreaks to chronic lifestyle ailments. Through this voyage of discovery, we unveil the vast potential of autophagy as a therapeutic linchpin, offering tantalizing prospects for targeted interventions and innovative treatment modalities that promise to transform the landscape of disease management.
Collapse
Affiliation(s)
- Jonaid Ahmad Malik
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, India
| | - Mohammad Adeel Zafar
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, India; Division of Immunology, Boston Children's Hospital Harvard Medical School Boston, MA, 02115, USA; Department of Pediatrics, Harvard Medical School Boston, MA, 02115, USA
| | - Sanpreet Singh
- Immunology Laboratory, Institute of Microbial Technology, Chandigarh, 160016, India; Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Sidhanta Nanda
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, India
| | - Hilal Bashir
- Immunology Laboratory, Institute of Microbial Technology, Chandigarh, 160016, India
| | - Deepjyoti Kumar Das
- Immunology Laboratory, Institute of Microbial Technology, Chandigarh, 160016, India
| | - Taruna Lamba
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, India
| | - Mohammad Affan Khan
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, India
| | - Gurpreet Kaur
- Department of Biotechnology, Chandigarh Group of Colleges, Landran, Mohali, Punjab, 140055, India
| | - Javed N Agrewala
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, India.
| |
Collapse
|
43
|
Jiang Z, Chen L, Wang T, Zhao J, Liu S, He Y, Wang L, Wu H. Autophagy accompanying the developmental process of male germline stem cells. Cell Tissue Res 2024; 398:1-14. [PMID: 39141056 DOI: 10.1007/s00441-024-03910-w] [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: 02/22/2024] [Accepted: 07/25/2024] [Indexed: 08/15/2024]
Abstract
Germline stem cells are a crucial type of stem cell that can stably pass on genetic information to the next generation, providing the necessary foundation for the reproduction and survival of organisms. Male mammalian germline stem cells are unique cell types that include primordial germ cells and spermatogonial stem cells. They can differentiate into germ cells, such as sperm and eggs, thereby facilitating offspring reproduction. In addition, they continuously generate stem cells through self-renewal mechanisms to support the normal function of the reproductive system. Autophagy involves the use of lysosomes to degrade proteins and organelles that are regulated by relevant genes. This process plays an important role in maintaining the homeostasis of germline stem cells and the synthesis, degradation, and recycling of germline stem cell products. Recently, the developmental regulatory mechanism of germline stem cells has been further elucidated, and autophagy has been shown to be involved in the regulation of self-renewal and differentiation of germline stem cells. In this review, we introduce autophagy accompanying the development of germline stem cells, focusing on the autophagy process accompanying the development of male spermatogonial stem cells and the roles of related genes and proteins. We also briefly outline the effects of autophagy dysfunction on germline stem cells and reproduction.
Collapse
Affiliation(s)
- Zhuofei Jiang
- Department of Gynecology, Foshan Woman and Children Hospital, Foshan, China
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Liji Chen
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Department of Reproductive Medicine, Guangzhou Huadu District Maternal and Child Health Care Hospital (Huzhong Hospital of Huadu District), Guangzhou, China
| | - Tao Wang
- Department of Surgery, Longjiang Hospital of Shunde District, Foshan, China
| | - Jie Zhao
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Shuxian Liu
- Department of Science and Education, Guangzhou Huadu District Maternal and Child Health Care Hospital (Huzhong Hospital of Huadu District), Guangzhou, China
| | - Yating He
- Department of Obstetrics, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
| | - Liyun Wang
- Department of Reproductive Medicine, Guangzhou Huadu District Maternal and Child Health Care Hospital (Huzhong Hospital of Huadu District), Guangzhou, China.
| | - Hongfu Wu
- Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China.
| |
Collapse
|
44
|
Dan VM, Sanawar R, Mohan GMG, Cheriyan SP, Kumar TRS. Urdamycin V from Streptomyces sp induces p53 independent apoptosis in cervical cancer cells inconsiderate of HPV status and inhibited growth of gram-positive human pathogens. Nat Prod Res 2024:1-5. [PMID: 39301579 DOI: 10.1080/14786419.2024.2405862] [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: 03/12/2024] [Revised: 08/23/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024]
Abstract
In cervical cancer, loss of p53 or mutant non-functional p53 and hyperactivated mTOR/Akt pathway positively correlates to cancer progression. Urdamycin V isolated from Streptomyces OA293 is a recently isolated novel angucycline derivative that in the present study showcased induction of p53 independent apoptosis in both HPV (Human papillomavirus) positive and negative cervical cancer cell lines. Apoptosis induction was via phosphorylation modulation in the cell growth regulating proteins along mTORC2/Akt/p38/Erk pathway. The compound was also tested against human pathogens and selectively inhibited gram-positive strains, Streptococcus pyogenes and Staphylococcus aureus. The present study put forward urdamycins as a potential therapeutic that places promise for further research.
Collapse
Affiliation(s)
- Vipin Mohan Dan
- Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram, India
| | - Rahul Sanawar
- Cancer Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Gama M G Mohan
- Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram, India
| | - Soniya P Cheriyan
- Microbiology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram, India
| | | |
Collapse
|
45
|
Dong MZ, Ouyang YC, Gao SC, Gu LJ, Guo JN, Sun SM, Wang ZB, Sun QY. Protein phosphatase 4 maintains the survival of primordial follicles by regulating autophagy in oocytes. Cell Death Dis 2024; 15:658. [PMID: 39245708 PMCID: PMC11381532 DOI: 10.1038/s41419-024-07051-4] [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: 03/23/2024] [Revised: 08/30/2024] [Accepted: 09/03/2024] [Indexed: 09/10/2024]
Abstract
In mammalian ovary, the primordial follicle pool serves as the source of developing follicles and fertilizable ova. To maintain the normal length of female reproductive life, the primordial follicles must have adequate number and be kept in a quiescent state before menopause. However, the molecular mechanisms underlying primordial follicle survival are poorly understood. Here, we provide genetic evidence showing that lacking protein phosphatase 4 (PPP4) in oocytes, a member of PP2A-like subfamily, results in infertility in female mice. A large quantity of primordial follicles has been depleted around the primordial follicle pool formation phase and the ovarian reserve is exhausted at about 7 months old. Further investigation demonstrates that depletion of PPP4 causes the abnormal activation of mTOR, which suppresses autophagy in primordial follicle oocytes. The abnormal primordial follicle oocytes are eventually erased by pregranulosa cells in the manner of lysosome invading. These results show that autophagy prevents primordial follicles over loss and PPP4-mTOR pathway governs autophagy during the primordial follicle formation and dormant period.
Collapse
Affiliation(s)
- Ming-Zhe Dong
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ying-Chun Ouyang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Shi-Cai Gao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lin-Jian Gu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jia-Ni Guo
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Si-Min Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhen-Bo Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qing-Yuan Sun
- Fertility Preservation Lab, Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| |
Collapse
|
46
|
Qi Z, Yang W, Xue B, Chen T, Lu X, Zhang R, Li Z, Zhao X, Zhang Y, Han F, Kong X, Liu R, Yao X, Jia R, Feng S. ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence. Autophagy 2024; 20:2000-2016. [PMID: 38762757 PMCID: PMC11346523 DOI: 10.1080/15548627.2024.2353548] [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: 06/06/2023] [Revised: 04/22/2024] [Accepted: 05/06/2024] [Indexed: 05/20/2024] Open
Abstract
Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.
Collapse
Affiliation(s)
- Zhangyang Qi
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Weiqi Yang
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Baibing Xue
- Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Tingjun Chen
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China
| | - Xianjie Lu
- The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/The Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Rong Zhang
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zhichao Li
- Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoqing Zhao
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yang Zhang
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Fabin Han
- The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/The Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Xiaohong Kong
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ruikang Liu
- Shandong Research Institute of Industrial Technology, Jinan, Shandong, China
| | - Xue Yao
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Orthopaedics, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China
| | - Rui Jia
- Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shiqing Feng
- Department of Orthopaedics, Qilu Hospital, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Orthopaedics, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China
- Department of Orthopaedics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| |
Collapse
|
47
|
Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [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: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
Collapse
Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| |
Collapse
|
48
|
Yuan Y, Zhang Q, Qiu F, Kang N, Zhang Q. Targeting TRPs in autophagy regulation and human diseases. Eur J Pharmacol 2024; 977:176681. [PMID: 38821165 DOI: 10.1016/j.ejphar.2024.176681] [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: 04/11/2024] [Revised: 05/06/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
Transient receptor potential channels (TRPs) are widely recognized as a group of ion channels involved in various sensory perceptions, such as temperature, taste, pressure, and vision. While macroautophagy (hereafter referred to as autophagy) is primarily regulated by core machinery, the ion exchange mediated by TRPs between intracellular and extracellular compartments, as well as within organelles and the cytoplasm, plays a crucial role in autophagy regulation as an important signaling transduction mechanism. Moreover, certain TRPs can directly interact with autophagy regulatory proteins to participate in autophagy regulation. In this article, we provide an in-depth review of the current understanding of the regulatory mechanisms of autophagy, with a specific focus on TRPs. Furthermore, we highlight the potential prospects for drug development targeting TRPs in autophagy for the treatment of human diseases.
Collapse
Affiliation(s)
- Yongkang Yuan
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Qiuju Zhang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China
| | - Feng Qiu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
| | - Ning Kang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
| | - Qiang Zhang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
| |
Collapse
|
49
|
Grobben Y. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Front Immunol 2024; 15:1440269. [PMID: 39211039 PMCID: PMC11359565 DOI: 10.3389/fimmu.2024.1440269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
Collapse
|
50
|
Zhang J, Pan X, Ji W, Zhou J. Autophagy mediated targeting degradation, a promising strategy in drug development. Bioorg Chem 2024; 149:107466. [PMID: 38843684 DOI: 10.1016/j.bioorg.2024.107466] [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: 03/18/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 06/17/2024]
Abstract
Targeted protein degradation (TPD) technologies have become promising therapeutic approaches through degrading disease-causing proteins via the protein degradation system. Autophagy is a fundamental biological process with a high relationship to protein degradation, which belongs to one of two main protein degradation pathways, the autophagy-lysosomal system. Recently, various autophagy-based TPD techniques ATTECs, AUTACs, and AUTOTACs, etc, have also been gradually developed, and they have achieved efficient degradation potency for the targeted protein, expanding the potential of degradation for large-size proteins or protein aggregates. Herein, we introduce the machinery of autophagy and its relation to protein degradation, and multiple methods for using autophagy to specifically degrade target proteins.
Collapse
Affiliation(s)
- Jiantao Zhang
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, PR China
| | - Xiangyi Pan
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, PR China
| | - Wenshu Ji
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, PR China
| | - Jinming Zhou
- Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, PR China.
| |
Collapse
|