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1
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Chen YW, Ahn IS, Wang SSM, Majid S, Diamante G, Cely I, Zhang G, Cabanayan A, Komzyuk S, Bonnett J, Arneson D, Yang X. Multitissue single-cell analysis reveals differential cellular and molecular sensitivity between fructose and high-fat high-sucrose diets. Cell Rep 2025; 44:115690. [PMID: 40349341 DOI: 10.1016/j.celrep.2025.115690] [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: 11/02/2023] [Revised: 03/03/2025] [Accepted: 04/21/2025] [Indexed: 05/14/2025] Open
Abstract
Metabolic syndrome (MetS), a conglomerate of dysregulated metabolic traits that vary between individuals, is partially driven by modern diets high in fat, sucrose, or fructose and their interactions with host genes in metabolic tissues. To elucidate the roles of individual tissues and cell types in diet-induced MetS, we performed single-cell RNA sequencing on the hypothalamus, liver, adipose tissue, and small intestine of mice fed high-fat high-sucrose (HFHS) or fructose diets. We found that hypothalamic neurons were sensitive to fructose, while adipose progenitor cells and macrophages were responsive to HFHS. Ligand-receptor analysis revealed lipid metabolism and inflammation networks among peripheral tissues driven by HFHS, while both diets stimulated synaptic remodeling within the hypothalamus. mt-Rnr2, a top responder to both diets, mitigated diet-induced MetS by stimulating thermogenesis. Our study demonstrates that HFHS and fructose diets have differential cell type and network targets but also share regulators such as mt-Rnr2 to affect MetS risk.
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Affiliation(s)
- Yen-Wei Chen
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA, USA
| | - In Sook Ahn
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Susanna Sue-Ming Wang
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sana Majid
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Graciel Diamante
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ingrid Cely
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Guanglin Zhang
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Angelus Cabanayan
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sergey Komzyuk
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jack Bonnett
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Douglas Arneson
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Xia Yang
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
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Ran Y, Guo Z, Zhang L, Li H, Zhang X, Guan X, Cui X, Chen H, Cheng M. Mitochondria‑derived peptides: Promising microproteins in cardiovascular diseases (Review). Mol Med Rep 2025; 31:127. [PMID: 40084698 PMCID: PMC11924172 DOI: 10.3892/mmr.2025.13492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/27/2025] [Indexed: 03/16/2025] Open
Abstract
Mitochondria‑derived peptides (MDPs) are a unique class of peptides encoded by short open reading frames in mitochondrial DNA, including the mitochondrial open reading frame of the 12S ribosomal RNA type‑c (MOTS‑c). Recent studies suggest that MDPs offer therapeutic benefits in various diseases, including neurodegenerative disorders and types of cancer, due to their ability to increase cellular resilience. Mitochondrial dysfunction is a key factor in the onset and progression of cardiovascular diseases (CVDs), such as atherosclerosis and heart failure, as it disrupts energy metabolism, increases oxidative stress and promotes inflammation. MDPs such as humanin and MOTS‑c have emerged as important regulators of mitochondrial health, as they show protective effects against these processes. Recent studies have shown that MDPs can restore mitochondrial function, reduce oxidative damage and alleviate inflammation, thus counteracting the pathological mechanisms that drive CVDs. Therefore, MDPs hold promise as therapeutic agents that are capable of slowing, stopping, or even reversing CVD progression and their use presents a promising strategy for future treatments. However, the clinical application of MDPs remains challenging due to their low bioavailability, poor stability and high synthesis costs. Thus, it is necessary to improve drug delivery systems to enhance the bioavailability of MDPs. Moreover, integrating basic research with clinical trials is essential to bridge the gap between experimental findings and clinical applications.
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Affiliation(s)
- Yutong Ran
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Zhiliang Guo
- Department of Spinal Surgery, The 80th Group Army Hospital of Chinese PLA, Weifang, Shandong 261021, P.R. China
| | - Lijuan Zhang
- Stroke Centre, Second People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Hong Li
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaoyun Zhang
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiumei Guan
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Xiaodong Cui
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Hao Chen
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Min Cheng
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
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3
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Wang R, Qian Y, Guo X, Song F, Xiong Z, Cai S, Bian X, Wong MH, Cao Q, Cheng L, Lu G, Leung KS. STModule: identifying tissue modules to uncover spatial components and characteristics of transcriptomic landscapes. Genome Med 2025; 17:18. [PMID: 40033360 PMCID: PMC11874447 DOI: 10.1186/s13073-025-01441-9] [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: 07/29/2024] [Accepted: 02/17/2025] [Indexed: 03/05/2025] Open
Abstract
Here we present STModule, a Bayesian method developed to identify tissue modules from spatially resolved transcriptomics that reveal spatial components and essential characteristics of tissues. STModule uncovers diverse expression signals in transcriptomic landscapes such as cancer, intraepithelial neoplasia, immune infiltration, outcome-related molecular features and various cell types, which facilitate downstream analysis and provide insights into tumor microenvironments, disease mechanisms, treatment development, and histological organization of tissues. STModule captures a broader spectrum of biological signals compared to other methods and detects novel spatial components. The tissue modules characterized by gene sets demonstrate greater robustness and transferability across different biopsies. STModule: https://github.com/rwang-z/STModule.git .
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Affiliation(s)
- Ran Wang
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, New Territories, Hong Kong, 999077, China
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China
| | - Yan Qian
- Department of Gastrointestinal Surgery Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 519082, China
| | - Xiaojing Guo
- Health Data Science Center, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, China
| | - Fangda Song
- School of Data Science, The Chinese University of Hong Kong (Shenzhen), Shenzhen, 518172, China
| | - Zhiqiang Xiong
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China
| | - Shirong Cai
- Department of Gastrointestinal Surgery Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 519082, China
| | - Xiuwu Bian
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Man Hon Wong
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China
| | - Qin Cao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China.
- Shenzhen Research Institute, the Chinese University of Hong Kong, Shenzhen, 518172, China.
| | - Lixin Cheng
- Health Data Science Center, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518020, China.
| | - Gang Lu
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China.
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, New Territories, Hong Kong, 999077, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
- Shenzhen Research Institute, the Chinese University of Hong Kong, Shenzhen, 518172, China.
| | - Kwong Sak Leung
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, 999077, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
- Department of Applied Data Science, Hong Kong Shue Yan University, North Point, Hong Kong Island, Hong Kong, 999077, China.
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Bilgin B, Hekim MG, Bulut F, Kelestemur MM, Adam M, Ozcan S, Canpolat S, Ayar A, Ozcan M. Humanin attenuates metabolic, toxic, and traumatic neuropathic pain in mice by protecting against oxidative stress and increasing inflammatory cytokine. Neuropharmacology 2025; 263:110207. [PMID: 39510375 DOI: 10.1016/j.neuropharm.2024.110207] [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: 05/20/2024] [Revised: 09/12/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024]
Abstract
Neuropathic pain is associated with diverse etiologies, including sciatica, diabetes, and the use of chemotherapeutic agents. Despite the varied origins, mitochondrial dysfunction, oxidative stress, and inflammatory cytokines are recognized as key contributing factors in both the initiation and maintenance of neuropathic pain. The effects of the mitochondrial-derived peptide humanin on neuropathic pain, however, remain unclear, despite its demonstrated influence on these mechanisms in numerous disease models. This study aimed to evaluate the effects of humanin on pain behavior in murine models of metabolic (streptozotocin/STZ), toxic (oxaliplatin/OXA), traumatic (sciatic nerve cuffing/cuff), and neuropathic pain. A secondary objective was to assess whether humanin modulates oxidative damage and inflammatory cytokine levels in these neuropathic pain models. Humanin (4 mg/kg) was administered intraperitoneally (i.p.) to BALB/c male mice with induced neuropathic pain over a period of 15 days, with pain thresholds assessed using hot plate, cold plate, and Von Frey tests. Serum levels of antioxidant enzymes, oxidative stress markers, and inflammatory/anti-inflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA). In neuropathic pain-induced mice, humanin administration resulted in a statistically significant increase in pain threshold values in the STZ + Humanin, OXA + Humanin, and cuff + Humanin groups compared to their respective control groups (P < 0.05) over 15 days. Furthermore, humanin treatment significantly elevated antioxidant enzyme levels and anti-inflammatory cytokine concentrations, while reducing oxidative stress markers and pro-inflammatory cytokine levels compared to control groups (P < 0.01). These findings suggest that humanin exhibits therapeutic potential in the treatment of neuropathic pain induced by STZ, OXA, and cuff models. The ability of humanin to mitigate neuropathic pain through the suppression of oxidative stress and inflammatory cytokines indicates its promise as a novel therapeutic strategy.
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Affiliation(s)
- Batuhan Bilgin
- Gaziantep Islam Science and Technology University Faculty of Medicine, Department of Biophysics, Gaziantep, Turkey.
| | | | - Ferah Bulut
- Firat University Faculty of Medicine, Department of Biophysics, Elazig, Turkey.
| | | | - Muhammed Adam
- Firat University Faculty of Medicine, Department of Biophysics, Elazig, Turkey.
| | - Sibel Ozcan
- Firat University Faculty of Medicine Department of Anesthesiology and Reanimation, Elazig, Turkey.
| | - Sinan Canpolat
- Firat University Faculty of Medicine, Department of Physiology, Elazig, Turkey.
| | - Ahmet Ayar
- Karadeniz Technical University, Faculty of Medicine, Department of Physiology, Trabzon, Turkey.
| | - Mete Ozcan
- Firat University Faculty of Medicine, Department of Biophysics, Elazig, Turkey.
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Yang M, Chen W, He L, Wang X, Liu D, Xiao L, Sun L. The Role of Mitokines in Diabetic Nephropathy. Curr Med Chem 2025; 32:1276-1287. [PMID: 37921178 DOI: 10.2174/0109298673255403230919061828] [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: 03/28/2023] [Revised: 08/06/2023] [Accepted: 08/17/2023] [Indexed: 11/04/2023]
Abstract
Diabetic nephropathy (DN) has gradually become one of the main causes of end-stage renal disease (ESRD). However, there is still a lack of effective preventive measures to delay its progression. As the energy factory in the cell, mitochondria play an irreplaceable role in maintaining cell homeostasis. Interestingly, recent studies have shown that in addition to maintaining homeostasis in cells in which mitochondria reside, when mitochondrial perturbations occur in one tissue, distal tissues can also sense and act through mitochondrial stress response pathways through a group of proteins or peptides called "mitokines". Here, we reviewed the mitokines that have been found thus far and summarized their research progress in DN. Finally, we explored the possibility of mitokines as potential therapeutic targets for DN.
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Affiliation(s)
- Ming Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xi Wang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Di Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Li Xiao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
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6
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Shi Q, Xiao Z, Cai W, Chen Y, Liang H, Ye Z, Li Z, Liang X. Quantitative proteomics analysis reveals the protective role of S14G-humanin in septic acute kidney injury using 4D-label-free and PRM Approaches. Biochem Biophys Res Commun 2024; 733:150630. [PMID: 39332154 DOI: 10.1016/j.bbrc.2024.150630] [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: 06/12/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/29/2024]
Abstract
Mitochondrial dysfunction contributes to septic acute kidney injury (S-AKI), making mitochondrial protection a potential therapeutic strategy. This study investigates the effects of S14G-humanin (HNG) in S-AKI, utilizing 4D-label-free and parallel reaction monitoring (PRM) techniques for proteomic analysis. An S-AKI model was created in male C57BL/6 mice using lipopolysaccharide (LPS) injection, followed by HNG administration. After 24 h, kidney tissues were analyzed for histology, biochemistry, mitochondrial function, and proteomics. HNG treatment improved renal function, reduced tubular injury, and decreased pro-inflammatory cytokines and oxidative stress markers. Proteomic analysis identified 5900 proteins, with 5111 quantifiable. HNG altered the expression of 132 proteins, with 18 selected for PRM validation. Ten of these proteins were linked to key pathways, including fatty acid degradation and PPAR signaling. This study is the first to show HNG's protective effects in S-AKI, providing insights into its mechanisms through advanced proteomic techniques.
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Affiliation(s)
- Qingying Shi
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Zhenmeng Xiao
- Blood Purification Center, the People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, 450003, China
| | - Wenjing Cai
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Yuanhan Chen
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Huaban Liang
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Zhiming Ye
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China
| | - Zhilian Li
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China.
| | - Xinling Liang
- Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106th, Zhongshan Road II, Guangzhou, 510080, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, 106th, Zhongshan Road II, Guangzhou, 510080, China.
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7
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Da W, Chen Q, Shen B. The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration. Biol Res 2024; 57:37. [PMID: 38824571 PMCID: PMC11143644 DOI: 10.1186/s40659-024-00494-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 04/03/2024] [Indexed: 06/03/2024] Open
Abstract
It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.
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Affiliation(s)
- Wacili Da
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Quan Chen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bin Shen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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8
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Romero-Becera R, Santamans AM, Arcones AC, Sabio G. From Beats to Metabolism: the Heart at the Core of Interorgan Metabolic Cross Talk. Physiology (Bethesda) 2024; 39:98-125. [PMID: 38051123 DOI: 10.1152/physiol.00018.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/26/2023] [Accepted: 12/01/2023] [Indexed: 12/07/2023] Open
Abstract
The heart, once considered a mere blood pump, is now recognized as a multifunctional metabolic and endocrine organ. Its function is tightly regulated by various metabolic processes, at the same time it serves as an endocrine organ, secreting bioactive molecules that impact systemic metabolism. In recent years, research has shed light on the intricate interplay between the heart and other metabolic organs, such as adipose tissue, liver, and skeletal muscle. The metabolic flexibility of the heart and its ability to switch between different energy substrates play a crucial role in maintaining cardiac function and overall metabolic homeostasis. Gaining a comprehensive understanding of how metabolic disorders disrupt cardiac metabolism is crucial, as it plays a pivotal role in the development and progression of cardiac diseases. The emerging understanding of the heart as a metabolic and endocrine organ highlights its essential contribution to whole body metabolic regulation and offers new insights into the pathogenesis of metabolic diseases, such as obesity, diabetes, and cardiovascular disorders. In this review, we provide an in-depth exploration of the heart's metabolic and endocrine functions, emphasizing its role in systemic metabolism and the interplay between the heart and other metabolic organs. Furthermore, emerging evidence suggests a correlation between heart disease and other conditions such as aging and cancer, indicating that the metabolic dysfunction observed in these conditions may share common underlying mechanisms. By unraveling the complex mechanisms underlying cardiac metabolism, we aim to contribute to the development of novel therapeutic strategies for metabolic diseases and improve overall cardiovascular health.
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Affiliation(s)
| | | | - Alba C Arcones
- Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
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9
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Ding W, Yang X, Lai K, Jiang Y, Liu Y. The potential of therapeutic strategies targeting mitochondrial biogenesis for the treatment of insulin resistance and type 2 diabetes mellitus. Arch Pharm Res 2024; 47:219-248. [PMID: 38485900 DOI: 10.1007/s12272-024-01490-5] [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: 12/10/2023] [Accepted: 03/07/2024] [Indexed: 04/07/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a persistent metabolic disorder marked by deficiencies in insulin secretion and/or function, affecting various tissues and organs and leading to numerous complications. Mitochondrial biogenesis, the process by which cells generate new mitochondria utilizing existing ones plays a crucial role in energy homeostasis, glucose metabolism, and lipid handling. Recent evidence suggests that promoting mitochondrial biogenesis can alleviate insulin resistance in the liver, adipose tissue, and skeletal muscle while improving pancreatic β-cell function. Moreover, enhanced mitochondrial biogenesis has been shown to ameliorate T2DM symptoms and may contribute to therapeutic effects for the treatment of diabetic nephropathy, cardiomyopathy, retinopathy, and neuropathy. This review summarizes the intricate connection between mitochondrial biogenesis and T2DM, highlighting the potential of novel therapeutic strategies targeting mitochondrial biogenesis for T2DM treatment and its associated complications. It also discusses several natural products that exhibit beneficial effects on T2DM by promoting mitochondrial biogenesis.
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Affiliation(s)
- Wenwen Ding
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaoxue Yang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Kaiyi Lai
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Yu Jiang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
| | - Ying Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, China.
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10
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Atakan MM, Türkel İ, Özerkliğ B, Koşar ŞN, Taylor DF, Yan X, Bishop DJ. Small peptides: could they have a big role in metabolism and the response to exercise? J Physiol 2024; 602:545-568. [PMID: 38196325 DOI: 10.1113/jp283214] [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: 10/19/2023] [Accepted: 12/14/2023] [Indexed: 01/11/2024] Open
Abstract
Exercise is a powerful non-pharmacological intervention for the treatment and prevention of numerous chronic diseases. Contracting skeletal muscles provoke widespread perturbations in numerous cells, tissues and organs, which stimulate multiple integrated adaptations that ultimately contribute to the many health benefits associated with regular exercise. Despite much research, the molecular mechanisms driving such changes are not completely resolved. Technological advancements beginning in the early 1960s have opened new avenues to explore the mechanisms responsible for the many beneficial adaptations to exercise. This has led to increased research into the role of small peptides (<100 amino acids) and mitochondrially derived peptides in metabolism and disease, including those coded within small open reading frames (sORFs; coding sequences that encode small peptides). Recently, it has been hypothesized that sORF-encoded mitochondrially derived peptides and other small peptides play significant roles as exercise-sensitive peptides in exercise-induced physiological adaptation. In this review, we highlight the discovery of mitochondrially derived peptides and newly discovered small peptides involved in metabolism, with a specific emphasis on their functions in exercise-induced adaptations and the prevention of metabolic diseases. In light of the few studies available, we also present data on how both single exercise sessions and exercise training affect expression of sORF-encoded mitochondrially derived peptides. Finally, we outline numerous research questions that await investigation regarding the roles of mitochondrially derived peptides in metabolism and prevention of various diseases, in addition to their roles in exercise-induced physiological adaptations, for future studies.
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Affiliation(s)
- Muhammed M Atakan
- Division of Exercise Nutrition and Metabolism, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
| | - İbrahim Türkel
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
| | - Berkay Özerkliğ
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
| | - Şükran N Koşar
- Division of Exercise Nutrition and Metabolism, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
| | - Dale F Taylor
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
| | - Xu Yan
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
- Sarcopenia Research Program, Australia Institute for Musculoskeletal Sciences (AIMSS), Melbourne, Victoria, Australia
| | - David J Bishop
- Institute for Health and Sport (iHeS), Victoria University, Melbourne, Victoria, Australia
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11
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Blatkiewicz M, Szyszka M, Olechnowicz A, Kamiński K, Jopek K, Komarowska H, Tyczewska M, Klimont A, Wierzbicki T, Karczewski M, Ruchała M, Rucinski M. Impaired Expression of Humanin during Adrenocortical Carcinoma. Int J Mol Sci 2024; 25:1038. [PMID: 38256114 PMCID: PMC10816135 DOI: 10.3390/ijms25021038] [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: 11/29/2023] [Revised: 01/11/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
The discovery of mitochondria-derived peptides (MDPs) has provided a new perspective on mitochondrial function. MDPs encoded by mitochondrial DNA (mtDNA) can act as hormone-like peptides, influencing cell survival and proliferation. Among these peptides, humanin has been identified as a crucial factor for maintaining cell survival and preventing cell death under various conditions. Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy that results from adrenal hormone dysfunction. This study aimed to investigate humanin expression in the adrenal tissue and serum of patients with ACC. For the first time, our study revealed significant reduction in the mRNA expression of humanin in patients with ACC compared to healthy controls. However, no significant changes were observed in the serum humanin levels. Interestingly, we identified a positive correlation between patient age and serum humanin levels and a negative correlation between tumor size and LDL levels. While the impaired expression of humanin in patients with ACC may be attributed to mitochondrial dysfunction, an alternative explanation could be related to diminished mitochondrial copy number. Further investigations are warranted to elucidate the intricate relationship among humanin, mitochondrial function, and ACC pathology.
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Affiliation(s)
- Małgorzata Blatkiewicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
| | - Marta Szyszka
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
| | - Anna Olechnowicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Kacper Kamiński
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Karol Jopek
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
| | - Hanna Komarowska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-356 Poznan, Poland; (H.K.); (A.K.); (M.R.)
| | - Marianna Tyczewska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
- Department of Anatomy and Histology, University of Zielona Góra, Licealna Street 9, 65-417 Zielona Góra, Poland
| | - Anna Klimont
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-356 Poznan, Poland; (H.K.); (A.K.); (M.R.)
| | - Tomasz Wierzbicki
- Department of General, Endocrinological and Gastroenterological Surgery, Poznan University of Medical Sciences, 60-355 Poznan, Poland;
| | - Marek Karczewski
- Department of General and Transplantation Surgery, Poznan University of Medical Sciences, 60-356 Poznan, Poland;
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-356 Poznan, Poland; (H.K.); (A.K.); (M.R.)
| | - Marcin Rucinski
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.S.); (K.J.); (M.R.)
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12
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Hekım MG, Ozcan S, Yur M, Yıldırım N, Ozcan M. Exploring the potential of humanin as a biomarker for early breast cancer detection: a study of serum levels and diagnostic performance. Biomarkers 2023; 28:555-561. [PMID: 37552125 DOI: 10.1080/1354750x.2023.2246700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 08/06/2023] [Indexed: 08/09/2023]
Abstract
INTRODUCTION Breast cancer is a leading cause of cancer death in women worldwide, and early detection is crucial for effective treatment. Mitochondrial dysfunction has been linked to cancer development and progression. Humanin, a mitochondrial-derived peptide, has been shown to have cytoprotective effects and may be involved in breast cancer development. In this study, we aimed to investigate the potential of humanin as a biomarker for breast cancer. METHODS We recruited 45 female patients diagnosed with primary invasive ductal breast cancer and 45 healthy volunteers. Serum humanin levels were measured using ELISA, and other cancer markers were measured using an Advia Centaur Immunology Analyser. RESULTS Our results showed that serum humanin levels were significantly higher in breast cancer patients than in healthy controls (p = 0.008). ROC curve analysis indicated that humanin could effectively discriminate between patients and healthy individuals, with a sensitivity of 62.5% and a specificity of 77.5%. CONCLUSION This suggests that humanin may be a potential new biomarker for breast cancer screening and early detection. Further research is needed to fully understand the relationship between humanin and breast cancer and to develop new diagnostic and therapeutic strategies.
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Affiliation(s)
| | - Sibel Ozcan
- Department of Anaesthesiology and Reanimation, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Mesut Yur
- Department of Surgical Oncology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Nilgun Yıldırım
- Department of Medical Oncology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Mete Ozcan
- Department of Biophysics, Faculty of Medicine, Firat University, Elazig, Turkey
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13
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Dabravolski SA. Mitochondria-derived peptides in healthy ageing and therapy of age-related diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 136:197-215. [PMID: 37437978 DOI: 10.1016/bs.apcsb.2023.02.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Abstract
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by mitochondrial DNA and involved in various stress-protecting mechanisms. To date, eight mitochondrial-derived peptides have been identified: MOTS-c sequence is hidden in the 12 S rRNA gene (MT-RNR1), and the other 7 (humanin and small humanin-like peptides 1-6) are encoded by the 16 S rRNA (MT-RNR2) gene. While the anti-apoptotic, anti-inflammatory and cardioprotective activities of MDPs are well described, recent research suggests that MDPs are sensitive metabolic sensors, closely connected with mtDNA mutation-associated diseases and age-associated metabolic disorders. In this chapter, we focus on the recent progress in understanding the metabolo-protective properties of MDPs, their role in maintenance of the cellular and mitochondrial homeostasis associated with age-related diseases: Alzheimer's disease, cognitive decline, macular degeneration and cataracts. Also, we will discuss MDPs-based and MDPs-targeted interventions to treat age-related diseases and extend a healthy lifespan.
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Affiliation(s)
- Siarhei A Dabravolski
- Department of Biotechnology Engineering, Braude Academic College of Engineering, Karmiel 2161002, Israel.
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14
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Wu J, Xiao D, Yu K, Shalamu K, He B, Zhang M. The protective effect of the mitochondrial-derived peptide MOTS-c on LPS-induced septic cardiomyopathy. Acta Biochim Biophys Sin (Shanghai) 2023; 55:285-294. [PMID: 36786072 PMCID: PMC10157545 DOI: 10.3724/abbs.2023006] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
<p indent="0mm">Septic cardiomyopathy is associated with mechanisms such as excessive inflammation, oxidative stress, regulation of calcium homeostasis, endothelial dysfunction, mitochondrial dysfunction, and cardiomyocyte death, and there is no effective treatment at present. MOTS-c is a mitochondria-derived peptide (MDP) encoded by mitochondrial DNA (mtDNA) that protects cells from stresses in an AMPK-dependent manner. In the present study, we aim to explore the protective effect of MOTS-c on lipopolysaccharide (LPS)-induced septic cardiomyopathy. LPS is used to establish a model of septic cardiomyopathy. Our results demonstrate that MOTS-c treatment reduces the mRNA levels of inflammatory cytokines ( <italic>IL-1β</italic>, <italic>IL-4</italic>, <italic>IL-6</italic>, and <italic>TNFα</italic>) in cardiomyocytes and the levels of circulating myocardial injury markers, such as CK-MB and TnT, alleviates cardiomyocyte mitochondrial dysfunction and oxidative stress, reduces cardiomyocyte apoptosis, activates cardioprotection-related signaling pathways, including AMPK, AKT, and ERK, and inhibits the inflammation-related signaling pathways JNK and STAT3. However, treatment with the AMPK pathway inhibitor compound C (CC) abolishes the positive effect of MOTS-c on LPS stress. Collectively, our research suggests that MOTS-c may attenuate myocardial injury in septic cardiomyopathy by activating AMPK and provides a new idea for therapeutic strategies in septic cardiomyopathy. </p>.
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15
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Wang X, Zhang M, Zhang M, Han Y, Chen X, Zhao W, Han Z, Sun J. Salvianolic acid A promotes mitochondrial biogenesis and function via regulating the AMPK/PGC‑1α signaling pathway in HUVECs. Exp Ther Med 2022; 24:485. [PMID: 35761806 PMCID: PMC9214604 DOI: 10.3892/etm.2022.11412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/18/2022] [Indexed: 12/04/2022] Open
Abstract
Mitochondrial dysregulation is an important pathology that leads to endothelial dysfunction, and the occurrence and development of cardiovascular diseases. Salvianolic acid A (SAA) has been demonstrated to be effective in the treatment of vascular complications of type 2 diabetes mellitus. Limited information has been reported on the effects of SAA on mitochondrial function in endothelial cells. In the present study, the effects of SAA on mitochondrial biogenesis and the related underlying mechanisms were investigated in human umbilical vein endothelial cells (HUVECs). Mitotracker red staining and transmission electron microscopy were used to evaluate the effect of SAA on mitochondrial quality. The effect of SAA treatment on mitochondrial DNA/nuclear DNA ratio of HUVECs was detected by real-time quantitative PCR. Western blot was used to determine the protein expression levels of complex III and Complex IV of mitochondrial oxidative phosphorylation subunit, and ATP production was determined by ATP test kit. Real-time quantitative PCR and Western blot were used to determine the effects of SAA on the expression of peroxisome proliferator-activated receptor γ coactivator (PGC-1α) and its target genes nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) proteins and genes. Finally, in the presence of 5'AMP-activated protein kinase (AMPK) specific inhibitors, the expression of PGC-1α, NRF1 and TFAM proteins and the phosphorylation levels of AMPK and Acetyl CoA Carboxylase (ACC) were detected by Western blot or real-time quantitative PCR. The results showed that SAA treatment significantly promoted mitochondrial biogenesis and enhanced mitochondrial function of HUVECs. SAA significantly increased the expression levels of PGC-1α and its target genes NRF1 and (TFAM), a key regulator of mitochondrial biogenesis in HUVECs. These enhancements were accompanied by significantly increased phosphorylation of AMPK and ACC, and were significantly inhibited by specific AMPK inhibitors. These results suggest that SAA may promote mitochondrial biogenesis in endothelial cells by activating the AMPK-mediated PGC-1α/TFAM signaling pathway. These data provide new insights into the mechanism of action of SAA in treating diabetic vascular complications.
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Affiliation(s)
- Xuelian Wang
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Mi Zhang
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Mengyao Zhang
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Yantao Han
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuehong Chen
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wenwen Zhao
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zhiwu Han
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jialin Sun
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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16
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Boutari C, Pappas PD, Theodoridis TD, Vavilis D. Humanin and diabetes mellitus: A review of in vitro and in vivo studies. World J Diabetes 2022; 13:213-223. [PMID: 35432758 PMCID: PMC8984571 DOI: 10.4239/wjd.v13.i3.213] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/24/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Humanin (HN) is a 24-amino acid mitochondrial-derived polypeptide with cyto-protective and anti-apoptotic effects that regulates the mitochondrial functions under stress conditions. Accumulating evidence suggests the role of HN against age-related diseases, such as Alzheimer’s disease. The decline in insulin action is a metabolic feature of aging and thus, type 2 diabetes mellitus is considered an age-related disease, as well. It has been suggested that HN increases insulin sensitivity, improves the survival of pancreatic beta cells, and delays the onset of diabetes, actions that could be deployed in the treatment of diabetes. The aim of this review is to present the in vitro and in vivo studies that examined the role of HN in insulin resistance and diabetes and to discuss its newly emerging role as a therapeutic option against those conditions.
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Affiliation(s)
- Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Panagiotis D Pappas
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
| | - Theodoros D Theodoridis
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
| | - Dimitrios Vavilis
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
- Medical School, University of Cyprus, Nicosia, Cyprus 20537 1678, Cyprus
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17
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Aharon-Hananel G, Romero-Afrima L, Saada A, Mantzur C, Raz I, Weksler-Zangen S. Cytochrome c Oxidase Activity as a Metabolic Regulator in Pancreatic Beta-Cells. Cells 2022; 11:cells11060929. [PMID: 35326380 PMCID: PMC8946064 DOI: 10.3390/cells11060929] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic β-cells couple glucose-stimulated insulin secretion (GSIS) with oxidative phosphorylation via cytochrome c oxidase (COX), a mitochondrial respiratory-chain enzyme. The Cohen diabetic-sensitive (CDs) rats exhibit hyperglycemia when fed a diabetogenic diet but maintain normoglycemia on a regular diet. We have previously reported a decreased COX activity in CDs rats and explored its relevance for type 2 diabetes (T2D). In this study, we investigated the relation between COX activity in islets, peripheral-blood mononuclear cells (PBMCs), and GSIS during diabetes development in CDs rats fed a diabetogenic diet for 4, 11, 20, and 30 days and during reversion to normoglycemia in hyperglycemic CDs rats fed a reversion diet for 7, 11, and 20 days. An oral glucose-tolerance test was performed at different periods of the diets measuring blood glucose and insulin concentrations. COX activity was determined in islets and PBMCs isolated from rats at the different periods of the diets. We demonstrated a progressive reduction in COX activity in CDs-islets that correlated positively with the decreasing GSIS (R2 = 0.9691, p < 0.001) and inversely with the elevation in blood glucose levels (R2 = 0.8396, p < 0.001). Hyperglycemia was initiated when islet COX activity decreased below 46%. The reversion diet restored >46% of the islet COX activity and GSIS while re-establishing normoglycemia. Interestingly, COX activity in PBMCs correlated significantly with islet COX activity (R2 = 0.8944, p < 0.001). Our data support islet COX activity as a major metabolic regulator of β-cells function. The correlation between COX activity in PBMCs and islets may serve as a noninvasive biomarker to monitor β-cell dysfunction in diabetes.
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Affiliation(s)
- Genya Aharon-Hananel
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan 5266202, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- The Department of Genetics, Hadassah Medical Center, Jerusalem 9112102, Israel;
| | - Leonor Romero-Afrima
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- The Department of Genetics, Hadassah Medical Center, Jerusalem 9112102, Israel;
| | - Ann Saada
- The Department of Genetics, Hadassah Medical Center, Jerusalem 9112102, Israel;
- Faculty of Medicine Hebrew, University of Jerusalem, Jerusalem 9112102, Israel
| | - Carmit Mantzur
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
| | - Itamar Raz
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- Faculty of Medicine Hebrew, University of Jerusalem, Jerusalem 9112102, Israel
| | - Sarah Weksler-Zangen
- The Hadassah Diabetes Center, Hadassah Medical Center, Jerusalem 9112102, Israel; (G.A.-H.); (L.R.-A.); (C.M.); (I.R.)
- Faculty of Medicine Hebrew, University of Jerusalem, Jerusalem 9112102, Israel
- The Liver Research Laboratory, Hadassah Medical Center, Jerusalem 9112102, Israel
- Correspondence: ; Tel.: +972-50-5172008
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18
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Gong Z, Goetzman E, Muzumdar RH. Cardio-protective role of Humanin in myocardial ischemia-reperfusion. Biochim Biophys Acta Gen Subj 2022; 1866:130066. [PMID: 34896254 DOI: 10.1016/j.bbagen.2021.130066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/18/2021] [Accepted: 12/02/2021] [Indexed: 01/07/2023]
Abstract
Mitochondria-derived peptides (MDPs) are bioactive peptides encoded by and secreted from the mitochondria. To date, a few MDPs including humanin, MOTS-c and SHLP1-6, and their diverse biological functions have been identified. The first and most studied MDP is humanin, a 24-amino-acid poly peptide. It was first identified in 2001 in the surviving neurons of patient with Alzheimer's disease, and since then has been well characterized for its neuro-protective effect through inhibition of apoptosis. Over the past two decades, humanin has been reported to play critical roles in aging as well as multiple diseases including metabolic disorders, cardiovascular diseases, and autoimmune disease. Humanin has been shown to modulate multiple biological processes including autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. A role for humanin has been shown in a wide range of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and myocardial fibrosis. In this minireview, we will summarize the literature demonstrating a role for humanin in cardio-protection following myocardial ischemia-reperfusion induced injury and the potential mechanisms that mediate it.
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Affiliation(s)
- Zhenwei Gong
- Division of Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
| | - Eric Goetzman
- Division of Genetic and Genomic Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Radhika H Muzumdar
- Division of Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
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19
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Kim SJ, Devgan A, Miller B, Lee SM, Kumagai H, Wilson KA, Wassef G, Wong R, Mehta HH, Cohen P, Yen K. Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension. Biochim Biophys Acta Gen Subj 2022; 1866:130017. [PMID: 34624450 PMCID: PMC8595716 DOI: 10.1016/j.bbagen.2021.130017] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/10/2021] [Accepted: 09/20/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND Autophagy, a highly conserved homeostatic mechanism, is essential for cell survival. The decline of autophagy function has been implicated in various diseases as well as aging. Although mitochondria play a key role in the autophagy process, whether mitochondrial-derived peptides are involved in this process has not been explored. METHODS We developed a high through put screening method to identify potential autophagy inducers among mitochondrial-derived peptides. We used three different cell lines, mice, c.elegans, and a human cohort to validate the observation. RESULTS Humanin, a mitochondrial-derived peptide, increases autophagy and maintains autophagy flux in several cell types. Humanin administration increases the expression of autophagy-related genes and lowers accumulation of harmful misfolded proteins in mice skeletal muscle, suggesting that humanin-induced autophagy potentially contributes to the improved skeletal function. Moreover, autophagy is a critical role in humanin-induced lifespan extension in C. elegans. CONCLUSIONS Humanin is an autophagy inducer. GENERAL SIGNIFICANCE This paper presents a significant, novel discovery regarding the role of the mitochondrial derived peptide humanin in autophagy regulation and as a possible therapeutic target for autophagy in various age-related diseases.
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Affiliation(s)
- Su-Jeong Kim
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Anjali Devgan
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Brendan Miller
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Sam Mool Lee
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Hiroshi Kumagai
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | | | - Gabriella Wassef
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Richard Wong
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Hemal H Mehta
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Pinchas Cohen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
| | - Kelvin Yen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
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20
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Urban C, Hayes HV, Piraino G, Wolfe V, Lahni P, O'Connor M, Phares C, Zingarelli B. Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice. Front Immunol 2022; 13:984298. [PMID: 36119052 PMCID: PMC9478210 DOI: 10.3389/fimmu.2022.984298] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Endothelial dysfunction plays a central role in the pathogenesis of sepsis-mediated multiple organ failure. Several clinical and experimental studies have suggested that the glycocalyx is an early target of endothelial injury during an infection. Colivelin, a synthetic derivative of the mitochondrial peptide humanin, has displayed cytoprotective effects in oxidative conditions. In the current study, we aimed to determine the potential therapeutic effects of colivelin in endothelial dysfunction and outcomes of sepsis in vivo. Male C57BL/6 mice were subjected to a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP) and were treated with vehicle or colivelin (100-200 µg/kg) intraperitoneally at 1 h after CLP. We observed that vehicle-treated mice had early elevation of plasma levels of the adhesion molecules ICAM-1 and P-selectin, the angiogenetic factor endoglin and the glycocalyx syndecan-1 at 6 h after CLP when compared to control mice, while levels of angiopoietin-2, a mediator of microvascular disintegration, and the proprotein convertase subtilisin/kexin type 9, an enzyme implicated in clearance of endotoxins, raised at 18 h after CLP. The early elevation of these endothelial and glycocalyx damage biomarkers coincided with lung histological injury and neutrophil inflammation in lung, liver, and kidneys. At transmission electron microscopy analysis, thoracic aortas of septic mice showed increased glycocalyx breakdown and shedding, and damaged mitochondria in endothelial and smooth muscle cells. Treatment with colivelin ameliorated lung architecture, reduced organ neutrophil infiltration, and attenuated plasma levels of syndecan-1, tumor necrosis factor-α, macrophage inflammatory protein-1α and interleukin-10. These therapeutic effects of colivelin were associated with amelioration of glycocalyx density and mitochondrial structure in the aorta. At molecular analysis, colivelin treatment was associated with inhibition of the signal transducer and activator of transcription 3 and activation of the AMP-activated protein kinase in the aorta and lung. In long-term outcomes studies up to 7 days, co-treatment of colivelin with antimicrobial agents significantly reduced the disease severity score when compared to treatment with antibiotics alone. In conclusion, our data support that damage of the glycocalyx is an early pathogenetic event during sepsis and that colivelin may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.
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Affiliation(s)
- Catherine Urban
- Division of Pediatric Critical Care, Stony Brook Children's, Stony Brook University, Stony Brook, NY, United States
| | - Hannah V Hayes
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Giovanna Piraino
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Vivian Wolfe
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Patrick Lahni
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Michael O'Connor
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Ciara Phares
- Department of Systems Biology and Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Basilia Zingarelli
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
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21
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Wu D, Kampmann E, Qian G. Novel Insights Into the Role of Mitochondria-Derived Peptides in Myocardial Infarction. Front Physiol 2021; 12:750177. [PMID: 34777013 PMCID: PMC8582487 DOI: 10.3389/fphys.2021.750177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/28/2021] [Indexed: 01/02/2023] Open
Abstract
Mitochondria-derived peptides (MDPs) are a new class of bioactive peptides encoded by small open reading frames (sORFs) within known mitochondrial DNA (mtDNA) genes. MDPs may affect the expression of nuclear genes and play cytoprotective roles against chronic and age-related diseases by maintaining mitochondrial function and cell viability in the face of metabolic stress and cytotoxic insults. In this review, we summarize clinical and experimental findings indicating that MDPs act as local and systemic regulators of glucose homeostasis, immune and inflammatory responses, mitochondrial function, and adaptive stress responses, and focus on evidence supporting the protective effects of MDPs against myocardial infarction. These insights into MDPs actions suggest their potential in the treatment of cardiovascular diseases and should encourage further research in this field.
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Affiliation(s)
- Dan Wu
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China
| | - Enny Kampmann
- School of Life Sciences, City College of San Francisco, San Francisco, CA, United States
| | - Geng Qian
- Department of Cardiology, The First Medical Center, Chinese People's Liberation Army Hospital, Medical School of Chinese People's Liberation Army, Beijing, China
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22
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Dabravolski SA, Nikiforov NG, Starodubova AV, Popkova TV, Orekhov AN. The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets. Int J Mol Sci 2021; 22:ijms22168770. [PMID: 34445477 PMCID: PMC8396025 DOI: 10.3390/ijms22168770] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Mitochondria-derived peptides (MDPs) are small peptides hidden in the mitochondrial DNA, maintaining mitochondrial function and protecting cells under different stresses. Currently, three types of MDPs have been identified: Humanin, MOTS-c and SHLP1-6. MDPs have demonstrated anti-apoptotic and anti-inflammatory activities, reactive oxygen species and oxidative stress-protecting properties both in vitro and in vivo. Recent research suggests that MDPs have a significant cardioprotective role, affecting CVDs (cardiovascular diseases) development and progression. CVDs are the leading cause of death globally; this term combines disorders of the blood vessels and heart. In this review, we focus on the recent progress in understanding the relationships between MDPs and the main cardiovascular risk factors (atherosclerosis, insulin resistance, hyperlipidaemia and ageing). We also will discuss the therapeutic application of MDPs, modified and synthetic MDPs, and their potential as novel biomarkers and therapeutic targets.
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Affiliation(s)
- Siarhei A. Dabravolski
- Department of Clinical Diagnostics, Vitebsk State Academy of Veterinary Medicine [UO VGAVM], 7/11 Dovatora Str., 210026 Vitebsk, Belarus
- Correspondence:
| | - Nikita G. Nikiforov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; (N.G.N.); (A.N.O.)
- Laboratory of Angiopathology, The Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia
| | - Antonina V. Starodubova
- Federal Research Centre for Nutrition, Biotechnology and Food Safety, 2/14 Ustinsky Passage, 109240 Moscow, Russia;
- Therapy Faculty, Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, 117997 Moscow, Russia
| | - Tatyana V. Popkova
- V.A. Nasonova Institute of Rheumatology, 34A Kashirskoye Shosse, 115522 Moscow, Russia;
| | - Alexander N. Orekhov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; (N.G.N.); (A.N.O.)
- Laboratory of Angiopathology, The Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia
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23
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Cai H, Liu Y, Men H, Zheng Y. Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases. Front Endocrinol (Lausanne) 2021; 12:683151. [PMID: 34177809 PMCID: PMC8222669 DOI: 10.3389/fendo.2021.683151] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
Physiological reactive oxygen species (ROS) are important regulators of intercellular signal transduction. Oxidative and antioxidation systems maintain a dynamic balance under physiological conditions. Increases in ROS levels destroy the dynamic balance, leading to oxidative stress damage. Oxidative stress is involved in the pathogenesis of aging-related cardiovascular diseases (ACVD), such as atherosclerosis, myocardial infarction, and heart failure, by contributing to apoptosis, hypertrophy, and fibrosis. Oxidative phosphorylation in mitochondria is the main source of ROS. Increasing evidence demonstrates the relationship between ACVD and humanin (HN), an endogenous peptide encoded by mitochondrial DNA. HN protects cardiomyocytes, endothelial cells, and fibroblasts from oxidative stress, highlighting its protective role in atherosclerosis, ischemia-reperfusion injury, and heart failure. Herein, we reviewed the signaling pathways associated with the HN effects on redox signals, including Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2), chaperone-mediated autophagy (CMA), c-jun NH2 terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). Furthermore, we discussed the relationship among HN, redox signaling pathways, and ACVD. Finally, we propose that HN may be a candidate drug for ACVD.
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24
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Hazafa A, Batool A, Ahmad S, Amjad M, Chaudhry SN, Asad J, Ghuman HF, Khan HM, Naeem M, Ghani U. Humanin: A mitochondrial-derived peptide in the treatment of apoptosis-related diseases. Life Sci 2021; 264:118679. [PMID: 33130077 DOI: 10.1016/j.lfs.2020.118679] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/19/2020] [Accepted: 10/25/2020] [Indexed: 02/07/2023]
Abstract
Humanin (HN) is a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA. HN exhibits protective effects in several cell types, including leukocytes, germ cells, neurons, tissues against cellular stress conditions and apoptosis through regulating various signaling mechanisms, such as JAK/STAT pathway and interaction of BCL-2 family of protein. HN is an essential cytoprotective peptide in the human body that regulates mitochondrial functions under stress conditions. The present review aims to evaluate HN peptide's antiapoptotic activities as a potential therapeutic target in the treatment of cancer, diabetes mellitus, male infertility, bone-related diseases, cardiac diseases, and brain diseases. Based on in vitro and in vivo studies, HN significantly suppressed the apoptosis during the treatment of bone osteoporosis, cardiovascular diseases, diabetes mellitus, and neurodegenerative diseases. According to accumulated data, it is concluded that HN exerts the proapoptotic activity of TNF-α in cancer, which makes HN as a novel therapeutic agent in the treatment of cancer and suggested that along with HN, the development of another mitochondrial-derived peptide could be a viable therapeutic option against different oxidative stress and apoptosis-related diseases.
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Affiliation(s)
- Abu Hazafa
- Department of Biochemistry, Faculty of Sciences, University of Agriculture, Faisalabad 38000, Pakistan.
| | - Ammara Batool
- Department of Biochemistry, Faculty of Sciences, University of Agriculture, Faisalabad 38000, Pakistan
| | - Saeed Ahmad
- Centre of Biotechnology & Microbiology, University of Peshawar, Pakistan
| | - Muhammad Amjad
- Centre of Agricultural Biochemistry and Biotechnology (CABB), University of Agriculture, Faisalabad 38000, Pakistan
| | - Sundas Nasir Chaudhry
- Department of Biochemistry, Faculty of Sciences, University of Agriculture, Faisalabad 38000, Pakistan
| | - Jamal Asad
- Department of Biochemistry, University of Health Sciences Lahore, Pakistan
| | - Hasham Feroz Ghuman
- Centre of Agricultural Biochemistry and Biotechnology (CABB), University of Agriculture, Faisalabad 38000, Pakistan
| | | | - Muhammad Naeem
- College of Life Science, Hebei Normal University, Shijiazhuang, China
| | - Usman Ghani
- Department of Biochemistry, Faculty of Sciences, University of Agriculture, Faisalabad 38000, Pakistan
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25
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The ubiquitin-proteasome system and its crosstalk with mitochondria as therapeutic targets in medicine. Pharmacol Res 2020; 163:105248. [PMID: 33065283 DOI: 10.1016/j.phrs.2020.105248] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022]
Abstract
The ubiquitin-proteasome system constitutes a major pathway for protein degradation in the cell. Therefore the crosstalk of this pathway with mitochondria is a major topic with direct relevance to many mitochondrial diseases. Proteasome dysfunction triggers not only protein toxicity, but also mitochondrial dysfunction. The involvement of proteasomes in the regulation of protein transport into mitochondria contributes to an increase in mitochondrial function defects. On the other hand, mitochondrial impairment stimulates reactive oxygen species production, which increases protein damage, and protein misfolding and aggregation leading to proteasome overload. Concurrently, mitochondrial dysfunction compromises cellular ATP production leading to reduced protein ubiquitination and proteasome activity. In this review we discuss the complex relationship and interdependence of the ubiquitin-proteasome system and mitochondria. Furthermore, we describe pharmacological inhibition of proteasome activity as a novel strategy to treat a group of mitochondrial diseases.
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26
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Li W, Zhang D, Yuan W, Wang C, Huang Q, Luo J. Humanin Ameliorates Free Fatty Acid-Induced Endothelial Inflammation by Suppressing the NLRP3 Inflammasome. ACS OMEGA 2020; 5:22039-22045. [PMID: 32923762 PMCID: PMC7482084 DOI: 10.1021/acsomega.0c01778] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/13/2020] [Indexed: 05/10/2023]
Abstract
Cardiovascular disease (CVD) has been considered as a major risk factor of death in recent decades. In CVDs, the NLRP3 inflammasome is important for inflammatory response and vascular damage. Therefore, safe and effective treatments to decrease NLRP3 inflammasome activation are required. Increased levels of free fatty acid (FFA) have been associated with the progression of CVD. Humanin, a kind of mitochondrial-derived peptide, has shown its beneficial effects in different types of cells. However, the roles of humanin in the NLRP3 inflammasome induced by FFA are still unknown. Here, we investigated the molecular mechanisms whereby humanin was found to exert protective effects in human aortic endothelial cells (HAECs) against FFA-caused endothelial injury. Here, treatment with humanin inhibited FFA-induced lactate dehydrogenase release, thereby demonstrating a protective capacity against cell death. Humanin also suppressed oxidative stress by downregulating the expression of reactive oxygen species and NOX2. Notably, humanin reduced NLRP3 and p10 and rescued FFA-induced dysfunction of adenosine monophosphate-activated protein kinase. Consequently, humanin inhibited the expression of IL-1β and IL-18. These results conclude that humanin might be a promising therapeutic agent for CVD.
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Affiliation(s)
| | | | | | | | | | - Jun Luo
- . Phone: +86-19979702109. Fax: +86-797-5889810
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27
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Sreekumar PG, Kannan R. Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration. Redox Biol 2020; 37:101663. [PMID: 32768357 PMCID: PMC7767738 DOI: 10.1016/j.redox.2020.101663] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 07/18/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial-derived peptides (MDPs) are a new class of small open reading frame encoded polypeptides with pleiotropic properties. The prominent members are Humanin (HN) and small HN-like peptide (SHLP) 2, which encode 16S rRNA, while mitochondrial open reading frame of the twelve S c (MOTS-c) encodes 12S rRNA of the mitochondrial genome. While the multifunctional properties of HN and its analog 14-HNG have been well documented, their protective role in the retinal pigment epithelium (RPE)/retina has been investigated only recently. In this review, we have summarized the multiple effects of HN and its analogs, SHLP2 and MOTS-c in oxidatively stressed human RPE and the regulatory pathways of signaling, mitochondrial function, senescence, and inter-organelle crosstalk. Emphasis is given to the mitochondrial functions such as biogenesis, bioenergetics, and autophagy in RPE undergoing oxidative stress. Further, the potential use of HN and its analogs in the prevention of age-related macular degeneration (AMD) are also presented. In addition, the role of novel, long-acting HN elastin-like polypeptides in nanotherapy of AMD and other ocular diseases stemming from oxidative damage is discussed. It is expected MDPs will become a promising group of mitochondrial peptides with valuable therapeutic applications in the treatment of retinal diseases.
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Affiliation(s)
- Parameswaran G Sreekumar
- The Stephen J. Ryan Initiative for Macular Research (RIMR), Doheny Eye Institute, Los Angeles, CA, 90033, USA
| | - Ram Kannan
- The Stephen J. Ryan Initiative for Macular Research (RIMR), Doheny Eye Institute, Los Angeles, CA, 90033, USA; Stein Eye Institute, Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
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28
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Rochette L, Meloux A, Zeller M, Cottin Y, Vergely C. Role of humanin, a mitochondrial-derived peptide, in cardiovascular disorders. Arch Cardiovasc Dis 2020; 113:564-571. [PMID: 32680738 DOI: 10.1016/j.acvd.2020.03.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/20/2020] [Accepted: 03/20/2020] [Indexed: 11/29/2022]
Abstract
The mitochondria produce specific peptides-mitochondrial-derived peptides-that mediate the transcriptional stress response by their translocation into the nucleus and interaction with deoxyribonucleic acid. Mitochondrial-derived peptides are regulators of metabolism. This class of peptides comprises humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides (SHLPs). Humanin inhibits mitochondrial complex 1 activity and limits the level of oxidative stress in the cell. Data show that mitochondrial-derived peptides have a role in improving metabolic diseases, such as type 2 diabetes. Perhaps humanin can be used as a marker for mitochondrial function in cardiovascular disease or as a pharmacological strategy in patients with endothelial dysfunction. The goal of this review is to discuss the newly emerging functions of humanin, and its biological role in cardiovascular disorders.
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Affiliation(s)
- Luc Rochette
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne - Franche Comté, Faculté des Sciences de Santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France.
| | - Alexandre Meloux
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne - Franche Comté, Faculté des Sciences de Santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France
| | - Marianne Zeller
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne - Franche Comté, Faculté des Sciences de Santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France
| | - Yves Cottin
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne - Franche Comté, Faculté des Sciences de Santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France; Department of Cardiology, CHU Dijon Bourgogne, 21000 Dijon, France
| | - Catherine Vergely
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne - Franche Comté, Faculté des Sciences de Santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France
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29
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Popov LD. Mitochondrial biogenesis: An update. J Cell Mol Med 2020; 24:4892-4899. [PMID: 32279443 PMCID: PMC7205802 DOI: 10.1111/jcmm.15194] [Citation(s) in RCA: 444] [Impact Index Per Article: 88.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/07/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
In response to the energy demand triggered by developmental signals and environmental stressors, the cells launch the mitochondrial biogenesis process. This is a self‐renewal route, by which new mitochondria are generated from the ones already existing. Recently, considerable progress has been made in deciphering mitochondrial biogenesis‐related proteins and genes that function in health and in pathology‐related circumstances. However, an outlook on the intracellular mechanisms shared by the main players that drive mitochondrial biogenesis machinery is still missing. Here, we provide such a view by focusing on the following issues: (a) the role of mitochondrial biogenesis in homeostasis of the mitochondrial mass and function, (b) the signalling pathways beyond the induction/promotion, stimulation and inhibition of mitochondrial biogenesis and (c) the therapeutic applications aiming the repair and regeneration of defective mitochondrial biogenesis (in ageing, metabolic diseases, neurodegeneration and cancer). The review is concluded by the perspectives of mitochondrial medicine and research.
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Affiliation(s)
- Lucia-Doina Popov
- "Nicolae Simionescu" Institute of Cellular Biology and Pathology of the Romanian Academy, Bucharest, Romania
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30
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Duan J, Chen Z, Wu Y, Zhu B, Yang L, Yang C. Metabolic remodeling induced by mitokines in heart failure. Aging (Albany NY) 2019; 11:7307-7327. [PMID: 31498116 PMCID: PMC6756899 DOI: 10.18632/aging.102247] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 08/22/2019] [Indexed: 04/11/2023]
Abstract
The prevalence rates of heart failure (HF) are greater than 10% in individuals aged >75 years, indicating an intrinsic link between aging and HF. It has been recognized that mitochondrial dysfunction contributes to the pathology of HF. Mitokines are a type of cytokines, peptides, or signaling pathways produced or activated by the nucleus or the mitochondria through cell non-autonomous responses during cellular stress. In addition to promoting the communication between the mitochondria and the nucleus, mitokines also exert a systemic regulatory effect by circulating to distant tissues. It is noteworthy that increasing evidence has demonstrated that mitokines are capable of reducing the metabolic-related HF risk factors and are associated with HF severity. Consequently, mitokines might represent a potential therapy target for HF.
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Affiliation(s)
- Jiahao Duan
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Zijun Chen
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Yeshun Wu
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Bin Zhu
- Department of Critical Care Medicine, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Ling Yang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Chun Yang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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31
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Gurunathan S, Jeyaraj M, Kang MH, Kim JH. Mitochondrial Peptide Humanin Protects Silver Nanoparticles-Induced Neurotoxicity in Human Neuroblastoma Cancer Cells (SH-SY5Y). Int J Mol Sci 2019; 20:ijms20184439. [PMID: 31505887 PMCID: PMC6770400 DOI: 10.3390/ijms20184439] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/15/2022] Open
Abstract
The extensive usage of silver nanoparticles (AgNPs) as medical products such as antimicrobial and anticancer agents has raised concerns about their harmful effects on human beings. AgNPs can potentially induce oxidative stress and apoptosis in cells. However, humanin (HN) is a small secreted peptide that has cytoprotective and neuroprotective cellular effects. The aim of this study was to assess the harmful effects of AgNPs on human neuroblastoma SH-SY5Y cells and also to investigate the protective effect of HN from AgNPs-induced cell death, mitochondrial dysfunctions, DNA damage, and apoptosis. AgNPs were prepared with an average size of 18 nm diameter to study their interaction with SH-SY5Y cells. AgNPs caused a dose-dependent decrease of cell viability and proliferation, induced loss of plasma-membrane integrity, oxidative stress, loss of mitochondrial membrane potential (MMP), and loss of ATP content, amongst other effects. Pretreatment or co-treatment of HN with AgNPs protected cells from several of these AgNPs induced adverse effects. Thus, this study demonstrated for the first time that HN protected neuroblastoma cells against AgNPs-induced neurotoxicity. The mechanisms of the HN-mediated protective effect on neuroblastoma cells may provide further insights for the development of novel therapeutic agents against neurodegenerative diseases.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Muniyandi Jeyaraj
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea.
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32
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Merdzo I, Rutkai I, Sure VNLR, Katakam PVG, Busija DW. Effects of prolonged type 2 diabetes on mitochondrial function in cerebral blood vessels. Am J Physiol Heart Circ Physiol 2019; 317:H1086-H1092. [PMID: 31490734 DOI: 10.1152/ajpheart.00341.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
One of the major characteristics of hyperglycemic states such as type 2 diabetes is increased reactive oxygen species (ROS) generation. Since mitochondria are a major source of ROS, it is vital to understand the involvement of these organelles in the pathogenesis of ROS-mediated conditions. Therefore, we investigated mitochondrial function and ROS production in cerebral blood vessels of 21-wk-old Zucker diabetic fatty obese rats and their lean controls. We have previously shown that in the early stages of insulin resistance, and short periods of type 2 diabetes mellitus, only mild differences exist in mitochondrial function. In the present study, we examined mitochondrial respiration, mitochondrial protein expression, and ROS production in large-surface cerebral arteries. We used 21-wk-old animals exposed to peak glucose levels for 7 wk and compared them with our previous studies on younger diabetic animals. We found that the same segments of mitochondrial respiration (basal respiration and proton leak) were diminished in diabetic groups as they were in younger diabetic animals. Levels of rattin, a rat humanin analog, tended to decrease in the diabetic group but did not reach statistical significance (P = 0.08). Other mitochondrial proteins were unaffected, which might indicate the existence of compensatory mechanisms with extension of this relatively mild form of diabetes. Superoxide levels were significantly higher in large cerebral vessels of diabetic animals compared with the control group. In conclusion, prolonged dietary diabetes leads to stabilization, rather than deterioration, of metabolic status in the cerebral circulation, despite continued overproduction of ROS.NEW & NOTEWORTHY We have characterized for the first time the dynamics of mitochondrial function during the progression of type 2 diabetes mellitus with regard to mitochondrial respiration, protein expression, and reactive oxygen species production. In addition, this is the first measurement of rattin levels in the cerebral vasculature, which could potentially lead to novel treatment options.
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Affiliation(s)
- Ivan Merdzo
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana.,Department of Pharmacology, University of Mostar, School of Medicine, Mostar, Bosnia and Herzegovina
| | - Ibolya Rutkai
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Venkata N L R Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Prasad V G Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - David W Busija
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
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33
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Benayoun BA, Lee C. MOTS-c: A Mitochondrial-Encoded Regulator of the Nucleus. Bioessays 2019; 41:e1900046. [PMID: 31378979 PMCID: PMC8224472 DOI: 10.1002/bies.201900046] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/28/2019] [Indexed: 12/25/2022]
Abstract
Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome-bearing organelles would likely include gene expression regulation. Multiple nuclear-encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial-encoded factors are known to actively regulate nuclear gene expression. MOTS-c (mitochondrial open reading frame of the 12S ribosomal RNA type-c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS-c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene-encoded factors that cross-regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator.
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Affiliation(s)
- Bérénice A Benayoun
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
- USC Norris Comprehensive Cancer Center, Epigenetics and Gene Regulation Program, Los Angeles, CA, 90089, USA
- USC Stem Cell Initiative, Los Angeles, CA, 90089, USA
| | - Changhan Lee
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA
- USC Norris Comprehensive Cancer Center, Epigenetics and Gene Regulation Program, Los Angeles, CA, 90089, USA
- Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, Republic of Korea
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34
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Kang N, Kim KW, Shin DM. Humanin suppresses receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation via AMP-activated protein kinase activation. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2019; 23:411-417. [PMID: 31496878 PMCID: PMC6717796 DOI: 10.4196/kjpp.2019.23.5.411] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 07/30/2019] [Accepted: 07/30/2019] [Indexed: 12/21/2022]
Abstract
Humanin (HN) is a mitochondrial peptide that exhibits cytoprotective actions against various stresses and diseases. HN has been shown to induce the phosphorylation of AMP-activated protein kinase (AMPK), which is a negative regulator of receptor activator of nuclear factor-κB ligand (RANKL). However, the role of HN in osteoclastogenesis or other skeletal disorders remains unknown. Here, we examined whether HN regulates osteoclastogenesis via AMPK activation using bone marrow-derived macrophage (BMM) cultures. Our results show that HN inhibited RANKL-induced osteoclast formation and reduced the expression of genes involved in osteoclastogenesis, including nuclear factor of activated T-cells cytoplasmic 1, osteoclast-associated receptor, cathepsin K, and tartrate-resistant acid phosphatase. Moreover, HN increased the levels of phosphorylated AMPK protein; compound C, an AMPK inhibitor, recovered HN-induced osteoclast differentiation. In addition, we found that HN significantly decreased the levels of RANKL-induced reactive oxygen species in BMMs. Therefore, these results indicate that HN plays an important role in osteoclastogenesis and may function as an inhibitor of bone disorders via AMPK activation.
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Affiliation(s)
- Namju Kang
- Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Korea
| | - Ki Woo Kim
- Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Korea
| | - Dong Min Shin
- Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Korea
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Mehta HH, Xiao J, Ramirez R, Miller B, Kim SJ, Cohen P, Yen K. Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment. Metabolomics 2019; 15:88. [PMID: 31172328 PMCID: PMC6554247 DOI: 10.1007/s11306-019-1549-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 05/24/2019] [Indexed: 01/10/2023]
Abstract
INTRODUCTION The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both humanin and small-humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. OBJECTIVES By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs' insulin sensitization effects. METHODS Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. RESULTS HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. CONCLUSIONS The present study indicates that humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for humanin and SHLP2 treatment.
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Affiliation(s)
- Hemal H Mehta
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Jialin Xiao
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Ricardo Ramirez
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Brendan Miller
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Su-Jeong Kim
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Pinchas Cohen
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Kelvin Yen
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
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Lu H, Wei M, Zhai Y, Li Q, Ye Z, Wang L, Luo W, Chen J, Lu Z. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med (Berl) 2019; 97:473-485. [PMID: 30725119 DOI: 10.1007/s00109-018-01738-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/04/2018] [Accepted: 12/21/2018] [Indexed: 12/21/2022]
Abstract
The postmenopausal state is associated with an increased risk of metabolic disorder including reduced energy expenditure and weight gain, leading to higher cardiovascular and cancer risks among other diseases. Mitochondrial-derived peptide (MOTS-c) is a 16-amino acid peptide encoded by mitochondrial DNA. Here, we showed that MOTS-c treatment in mice prevented ovariectomy-induced obesity and insulin resistance. After ovariectomy, low levels of estrogens increased fat mass overload and disturbed normal adipose function, forcing the development of insulin resistance. MOTS-c treatment increased brown fat activation and reduced OVX-induced fat accumulation and inflammatory invasion in white adipose tissue, which contributes to the lower level of fatty acid in serum and liver. Moreover, MOTS-c activated AMPK pathway to improve energy dissipation and insulin sensitivity. And a blocker of AMPK pathway was found to attenuate the role of MOTS-c in the regulation of adipocyte lipid metabolism. In conclusion, MOTS-c is a high potential candidate for chronic treatment of menopausal induced metabolic dysfunction. KEY MESSAGES: • MOTS-c prevents ovariectomy (OVX)-induced body weight gain and insulin resistance. • MOTS-c reduces fat mass and suppresses inflammatory response under OVX condition. • MOTS-c sustains the activity of the brown adipose under OVX condition. • MOTS-c mediates AMPK pathway activation to control adipose metabolic homeostasis.
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Affiliation(s)
- Huanyu Lu
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Ming Wei
- Department of Pharmacology, Xi'an Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yue Zhai
- Department of Cell Biology, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Qingyang Li
- Company 22, Brigade 6, School of Basic Medicine, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Zichen Ye
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, People's Republic of China
| | - Li Wang
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, People's Republic of China
| | - Wenjing Luo
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Jingyuan Chen
- Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, Shaanxi, People's Republic of China.
| | - Zifan Lu
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Air Force Medical University, No. 169 West Chang-le Road, Xi'an, 710032, People's Republic of China.
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A Mitochondrial Encoded Messenger at the Nucleus. Cells 2018; 7:cells7080105. [PMID: 30104535 PMCID: PMC6115982 DOI: 10.3390/cells7080105] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 08/10/2018] [Accepted: 08/11/2018] [Indexed: 12/21/2022] Open
Abstract
Mitochondria–nucleus (mitonuclear) retrograde signaling via nuclear import of otherwise mitochondrial targeted factors occurs during mitochondrial unfolded protein response (UPRmt), a mechanism that counters mitochondrial and cellular stresses. Other than nuclear encoded proteins, mitochondrial DNA (mtDNA)-encoded peptides, such as humanin, are known to have important pro-survival and metabolic regulatory functions. A recent report has indicated that another mtDNA-encoded peptide, the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), could translocate into the nucleus upon stress induction. In the nucleus, MOTS-c binds to DNA and regulates the transcription of stress response genes in concert with other transcription factors. This is the first clear example of a mitochondria-derived peptide (MDP) acting in the nucleus to affect transcriptional responses to stress. Thus, MOTS-c may bear some characteristics of a ‘mitokine’ factor that mediates mitohormesis, influencing cell survival as well as organismal health and longevity.
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