{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:30:06Z","timestamp":1792038606593,"version":"4.4.0"},"reference-count":103,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T00:00:00Z","timestamp":1654992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG055747"],"award-info":[{"award-number":["R01AG055747"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P30AG013319"],"award-info":[{"award-number":["P30AG013319"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["#1-18 IBS-329"],"award-info":[{"award-number":["#1-18 IBS-329"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Diabetes Association","award":["R01AG055747"],"award-info":[{"award-number":["R01AG055747"]}]},{"name":"American Diabetes Association","award":["P30AG013319"],"award-info":[{"award-number":["P30AG013319"]}]},{"name":"American Diabetes Association","award":["#1-18 IBS-329"],"award-info":[{"award-number":["#1-18 IBS-329"]}]},{"name":"Barth Syndrome Foundation","award":["R01AG055747"],"award-info":[{"award-number":["R01AG055747"]}]},{"name":"Barth Syndrome Foundation","award":["P30AG013319"],"award-info":[{"award-number":["P30AG013319"]}]},{"name":"Barth Syndrome Foundation","award":["#1-18 IBS-329"],"award-info":[{"award-number":["#1-18 IBS-329"]}]},{"name":"Joe R. and Teresa Lozano Long Distinguished Chair in Metabolic Biology","award":["R01AG055747"],"award-info":[{"award-number":["R01AG055747"]}]},{"name":"Joe R. and Teresa Lozano Long Distinguished Chair in Metabolic Biology","award":["P30AG013319"],"award-info":[{"award-number":["P30AG013319"]}]},{"name":"Joe R. and Teresa Lozano Long Distinguished Chair in Metabolic Biology","award":["#1-18 IBS-329"],"award-info":[{"award-number":["#1-18 IBS-329"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells11121906","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T09:26:48Z","timestamp":1655026008000},"page":"1906","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8489-3699","authenticated-orcid":false,"given":"Jun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9979-5661","authenticated-orcid":false,"given":"Yuguang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1146\/annurev.genet.39.110304.095751","article-title":"A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine","volume":"39","author":"Wallace","year":"2005","journal-title":"Annu. 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