One should always be somewhat dubious when researchers claim the primacy of any single mechanism in age-related dysfunction. It is one thing to demonstrate that a mechanism exists and is damaging, and quite another to show that it provides a significant contribution to aging in animal models or humans. Aging is enormously complex, and it has traditionally proven very challenging to repair or ameliorate just one mechanism in isolation, in order to see what happens. Bear this in mind while reading this otherwise interesting paper on the function of ALCAT1 in age-related mitochondrial dysfunction.
Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mitochondrial DNA 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.
Link: https://doi.org/10.3390/cells11121906
View the full article at FightAging
