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Cells
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Mitochondrial Dysfunction in Aging and Metabolic Diseases
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Mitochondrial Dysfunction in Aging and Metabolic Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 13980

Special Issue Editors

Dr. Yuguang Shi

E-Mail Website
Guest Editor
Department of Pharmacology, Sam and Ann Barshop Institue for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX 78229, USA
Interests: mitochondrial dysfunction; cardiolipin remodeling; aging; metabolic diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Jun Zhang

E-Mail Website
Assistant Guest Editor
Department of Pharmacology, Sam and Ann Barshop Institue for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX 78229, USA
Interests: aging; mitochondrial dysfunction; cardiolipin remodeling; mitophagy; mitochondrial transport; innate immune response
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are crucial for cellular bioenergetics and play a major role in multiple cellular processes that dictate the fate of a cell. Mitochondrial dysfunction is characterized by a reduced efficiency of oxidative phosphorylation, generation of free radicals, and reductions in the synthesis of adenosine-5′-triphosphate. Accumulating evidences have suggested that mitochondrial dysfunction plays a critical role in the pathogenesis of aging and age-related metabolic diseases, including type 2 diabetes, obesity, and cardiovascular diseases. Mitochondria undergo periodical cycles of fission, fusion, and mitophagy as a quality control process. Defects in such a process cause accumulation of damaged mitochondria, which in turn decreases oxidative phosphorylation and increases the production of reactive oxygen species. Moreover, mitochondrial DNA (mtDNA) mutations increase in frequency with age, and increased levels of mtDNA mutations also contribute to the onset of aging and age-related diseases. In addition, mitochondrial phospholipids, including cardiolipin (CL) and phosphatidylglycerol (PG), play a pivotal role in maintain mitochondrial integrity and function. It has been shown that mitochondrial membrane lipid composition is linked to metabolic rate and life span in a wide variety of animal species. Oxidized CL activates several innate immune pathways, and causes chronic inflammation and cellular senescence in aging and age-related metabolic diseases.  Although the underlying molecular pathways in regulating mitochondrial function is complex, it is crucial to understand the nexus of mitochondrial dysfunction in aging and age‐related metabolic diseases.

The current Special Issue will accept original studies, reviews, and technical reports in the field of mitochondrial biology and dysfunction, including mitochondrial quality control, oxidative stress, mtDNA integrity, synthesis and remodelling of mitochondrial phospholipids in aging and age-related metabolic diseases, written by scientists active in the field.

Prof. Yuguang Shi
Guest Editor
Dr. Jun Zhang
Assistant Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Mitochondrial dysfunction
  • Aging
  • Metabolic diseases
  • Oxidative stress
  • Mitophagy
  • mtDNA
  • Cellular senescence
  • Mitochondrial phospholipids
  • Cardiolipin
  • Mitochondrial protein and lipid transport

Related Special Issue

Published Papers (5 papers)

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Research

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12 pages, 1363 KiB  
Article
Association between Immunosenescence, Mitochondrial Dysfunction and Frailty Syndrome in Older Adults
by Ilaria Buondonno, Francesca Sassi, Francesco Cattaneo and Patrizia D’Amelio
Cells 2023, 12(1), 44; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12010044 - 22 Dec 2022
Cited by 4 | Viewed by 1853
Abstract
Aging is associated with changes in the immune system, increased inflammation and mitochondrial dysfunction. The relationship between these phenomena and the clinical phenotype of frailty is unclear. Here, we evaluated the immune phenotypes, T cell functions and mitochondrial functions of immune cells in [...] Read more.
Aging is associated with changes in the immune system, increased inflammation and mitochondrial dysfunction. The relationship between these phenomena and the clinical phenotype of frailty is unclear. Here, we evaluated the immune phenotypes, T cell functions and mitochondrial functions of immune cells in frail and robust older subjects. We enrolled 20 frail subjects age- and gender-matched with 20 robust controls, and T cell phenotype, response to immune stimulation, cytokine production and immune cell mitochondrial function were assessed. Our results showed that numbers of CD4+ and CD8+ T cells were decreased in frail subjects, without impairment to their ratios. Memory and naïve T cells were not significantly affected by frailty, whereas the expression of CD28 but not that of ICOS was decreased in T cells from frail subjects. T cells from robust subjects produced more IL-17 after CD28 stimulation. Levels of serum cytokines were similar in frail subjects and controls. Mitochondrial bioenergetics and ATP levels were significantly lower in immune cells from frail subjects. In conclusion, we suggest that changes in T cell profiles are associated with aging rather than with frailty syndrome; however, changes in T cell response to immune stimuli and reduced mitochondrial activity in immune cells may be considered hallmarks of frailty. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Aging and Metabolic Diseases)
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14 pages, 4127 KiB  
Article
Changes in Mitochondrial Size and Morphology in the RPE and Photoreceptors of the Developing and Ageing Zebrafish
by Thomas Burgoyne, Maria Toms, Chris Way, Dhani Tracey-White, Clare E. Futter and Mariya Moosajee
Cells 2022, 11(22), 3542; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11223542 - 09 Nov 2022
Cited by 1 | Viewed by 2120
Abstract
Mitochondria are essential adenosine triphosphate (ATP)-generating cellular organelles. In the retina, they are highly numerous in the photoreceptors and retinal pigment epithelium (RPE) due to their high energetic requirements. Fission and fusion of the mitochondria within these cells allow them to adapt to [...] Read more.
Mitochondria are essential adenosine triphosphate (ATP)-generating cellular organelles. In the retina, they are highly numerous in the photoreceptors and retinal pigment epithelium (RPE) due to their high energetic requirements. Fission and fusion of the mitochondria within these cells allow them to adapt to changing demands over the lifespan of the organism. Using transmission electron microscopy, we examined the mitochondrial ultrastructure of zebrafish photoreceptors and RPE from 5 days post fertilisation (dpf) through to late adulthood (3 years). Notably, mitochondria in the youngest animals were large and irregular shaped with a loose cristae architecture, but by 8 dpf they had reduced in size and expanded in number with more defined cristae. Investigation of temporal gene expression of several mitochondrial-related markers indicated fission as the dominant mechanism contributing to the changes observed over time. This is likely to be due to continued mitochondrial stress resulting from the oxidative environment of the retina and prolonged light exposure. We have characterised retinal mitochondrial ageing in a key vertebrate model organism, that provides a basis for future studies of retinal diseases that are linked to mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Aging and Metabolic Diseases)
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16 pages, 6091 KiB  
Article
Exercise Enhances Branched-Chain Amino Acid Catabolism and Decreases Cardiac Vulnerability to Myocardial Ischemic Injury
by Guiling Wu, Yanjie Guo, Min Li, Chenhan Li, Yanzhen Tan, Yueyang Li, Jia Li, Li Wang, Xing Zhang and Feng Gao
Cells 2022, 11(10), 1706; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101706 - 20 May 2022
Cited by 8 | Viewed by 2503
Abstract
Long-term exercise-induced metabolic adaptations occupy a central position in exercise-afforded cardiac benefits. Emerging evidence suggests that branched-chain amino acid (BCAA) catabolic defect contributes to cardiac dysfunction in multiple cardiometabolic diseases. However, the role of BCAA catabolism in exercise-afforded cardiac benefits remains unknown. Here, [...] Read more.
Long-term exercise-induced metabolic adaptations occupy a central position in exercise-afforded cardiac benefits. Emerging evidence suggests that branched-chain amino acid (BCAA) catabolic defect contributes to cardiac dysfunction in multiple cardiometabolic diseases. However, the role of BCAA catabolism in exercise-afforded cardiac benefits remains unknown. Here, we show that exercise improves BCAA catabolism and thus reduce cardiac vulnerability to myocardial ischemic injury. Exercise increased circulating BCAA levels in both humans (male adolescent athletes) and mice (following an 8-week swimming intervention). It increased the expression of mitochondrial localized 2C-type serine-threonine protein phosphatase (PP2Cm), a key enzyme in regulating BCAA catabolism, and decreased BCAA accumulation in mouse hearts, indicating an increase in BCAA catabolism. Pharmacological promotion of BCAA catabolism protected the mouse heart against myocardial infarction (MI) induced by permanent ligation of the left descending coronary artery. Although cardiac-specific PP2Cm knockout showed no significant effects on cardiac structural and functional adaptations to exercise, it blunted the cardioprotective effects of exercise against MI. Mechanistically, exercise alleviated BCAA accumulation and subsequently inactivated the mammalian target of rapamycin in MI hearts. These results showed that exercise elevated BCAA catabolism and protected the heart against myocardial ischemic injury, reinforcing the role of exercise in the promotion of cardiac health. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Aging and Metabolic Diseases)
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14 pages, 4524 KiB  
Article
Integrative Analyses Reveal Tstd1 as a Potential Modulator of HDL Cholesterol and Mitochondrial Function in Mice
by Adi Zheng, Hao Li, Zhihui Feng and Jiankang Liu
Cells 2021, 10(11), 2976; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112976 - 01 Nov 2021
Cited by 3 | Viewed by 2048
Abstract
High-density lipoprotein (HDL) cholesterol levels are closely associated with human health and diseases. To identify genes modulating plasma HDL levels, we integrated HDL measurements and multi-omics data collected from diverse mouse cohorts and combined a list of systems genetics methods, including quantitative trait [...] Read more.
High-density lipoprotein (HDL) cholesterol levels are closely associated with human health and diseases. To identify genes modulating plasma HDL levels, we integrated HDL measurements and multi-omics data collected from diverse mouse cohorts and combined a list of systems genetics methods, including quantitative trait loci (QTL) mapping analysis, mediation analysis, transcriptome-wide association analysis (TWAS), and correlation analysis. We confirmed a significant and conserved QTL for plasma HDL on chromosome 1 and identified that Tstd1 liver transcript correlates with plasma HDL in several independent mouse cohorts, suggesting Tstd1 may be a potential modulator of plasma HDL levels. Correlation analysis using over 70 transcriptomics datasets in humans and mice revealed consistent correlations between Tstd1 and genes known to be involved in cholesterol and HDL regulation. Consistent with strong enrichment in gene sets related to cholesterol and lipoproteins in the liver, mouse strains with high Tstd1 exhibited higher plasma levels of HDL, total cholesterol and other lipid markers. GeneBridge using large-scale expression datasets identified conserved and positive associations between TSTD1/Tstd1 and mitochondrial pathways, as well as cholesterol and lipid pathways in human, mouse and rat. In summary, we identified Tstd1 as a new modulator of plasma HDL and mitochondrial function through integrative systems analyses, and proposed a new mechanism of HDL modulation and a potential therapeutic target for relevant diseases. This study highlights the value of such integrative approaches in revealing molecular mechanisms of complex traits or diseases. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Aging and Metabolic Diseases)
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Review

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14 pages, 1792 KiB  
Review
In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases
by Jun Zhang and Yuguang Shi
Cells 2022, 11(12), 1906; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11121906 - 12 Jun 2022
Cited by 12 | Viewed by 3985
Abstract
Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mtDNA bioenergetics, and mitophagy. The depletion or abnormal acyl composition of CL causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and [...] Read more.
Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mtDNA bioenergetics, and mitophagy. The depletion or abnormal acyl composition of CL causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and age-related disorders. However, the molecular mechanisms by which mitochondrial dysfunction causes age-related diseases remain poorly understood. Recent development in the field has identified acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase upregulated by oxidative stress, as a key enzyme that promotes mitochondrial dysfunction in age-related diseases. ALCAT1 catalyzes CL remodeling with very-long-chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL becomes a new source of ROS in the form of lipid peroxides, leading to a vicious cycle of oxidative stress, CL depletion, and mitochondrial dysfunction. Consequently, ablation or the pharmacological inhibition of ALCAT1 have been shown to mitigate obesity, type 2 diabetes, heart failure, cardiomyopathy, fatty liver diseases, neurodegenerative diseases, and cancer. The findings suggest that age-related disorders are one disease (aging) manifested by different mitochondrion-sensitive tissues, and therefore should be treated as one disease. This review will discuss a unified hypothesis on CL remodeling by ALCAT1 as the common denominator of mitochondrial dysfunction, linking mitochondrial dysfunction to the development of age-related diseases. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Aging and Metabolic Diseases)
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