In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases

被引:17
作者
Zhang, Jun [1 ]
Shi, Yuguang [1 ]
机构
[1] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, Dept Pharmacol, San Antonio, TX 78229 USA
关键词
ALCAT1; cardiolipin; mitochondrial dysfunction; aging; age-related diseases; ELECTRON-TRANSPORT CHAIN; ACETYL-L-CARNITINE; INCREASED OXIDATIVE STRESS; COMPLEX-I ACTIVITY; C-OXIDASE ACTIVITY; CYTOCHROME-C; RAT-HEART; SKELETAL-MUSCLE; TETRALINOLEOYL-CARDIOLIPIN; DOCOSAHEXAENOIC ACID;
D O I
10.3390/cells11121906
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:14
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