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In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases
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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221202/ https://www.ncbi.nlm.nih.gov/pubmed/35741033 http://dx.doi.org/10.3390/cells11121906 |
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author | Zhang, Jun Shi, Yuguang |
author_facet | Zhang, Jun Shi, Yuguang |
author_sort | Zhang, Jun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9221202 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92212022022-06-24 In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases Zhang, Jun Shi, Yuguang Cells Review 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. MDPI 2022-06-12 /pmc/articles/PMC9221202/ /pubmed/35741033 http://dx.doi.org/10.3390/cells11121906 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Zhang, Jun Shi, Yuguang In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases |
title | In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases |
title_full | In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases |
title_fullStr | In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases |
title_full_unstemmed | In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases |
title_short | In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases |
title_sort | in search of the holy grail: toward a unified hypothesis on mitochondrial dysfunction in age-related diseases |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221202/ https://www.ncbi.nlm.nih.gov/pubmed/35741033 http://dx.doi.org/10.3390/cells11121906 |
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