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.
Cells. 2022 Jun 12;11(12):1906. doi: 10.3390/cells11121906.
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.
心磷脂（CL）是一种线粒体特征性磷脂，在心磷脂代谢与线粒体功能障碍方面扮演着关键角色。在心磷脂代谢与线粒体功能障碍方面扮演着关键角色。CL 的耗竭或酰基组成异常会导致线粒体功能障碍，这与衰老和与年龄相关疾病的发病机制有关。然而，线粒体功能障碍导致与年龄相关疾病的分子机制仍知之甚少。该领域的最新进展已经确定了酰基辅酶 A：溶血心磷脂酰基转移酶 1（ALCAT1），一种由氧化应激上调的酰基转移酶，是促进与年龄相关疾病中线粒体功能障碍的关键酶。ALCAT1 催化 CL 与非常长链多不饱和脂肪酸（如二十二碳六烯酸（DHA））的重塑。DHA 的富集使 CL 非常容易受到活性氧（ROS）的氧化损伤。氧化的 CL 成为以脂质过氧化物形式存在的 ROS 的新来源，导致氧化应激、CL 耗竭和线粒体功能障碍的恶性循环。因此，ALCAT1 的消融或药理抑制已被证明可以减轻肥胖、2 型糖尿病、心力衰竭、心肌病、脂肪肝疾病、神经退行性疾病和癌症。这些发现表明，与年龄相关的疾病是一种以不同的对线粒体敏感的组织表现出来的疾病（衰老），因此应该被视为一种疾病。这篇综述将讨论一个统一的假说，即 ALCAT1 介导的心磷脂重塑是线粒体功能障碍的共同特征，将线粒体功能障碍与与年龄相关疾病的发展联系起来。
