Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction

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

“…CL is the only phospholipid with four acyl chains, which, in theory, can generate millions of CL species (1 × 4 20–40 ) ( Figure 1 A). However, the four fatty acyl chains of CL are restricted to C18 chains dominated by the linoleoyl group (C18:2) in the heart, skeletal muscle, and liver [ 16 , 17 , 18 , 22 ]. This unique fatty acyl composition, also known as tetralinoleoyl CL (TLCL, Figure 1 B), plays an important role in the maximum efficiency of respiration.…”

“…In comparison to the MLCLAT, which catalyzes exclusively the synthesis of TLCL by using linoleoyl-CoA and MLCL as substrates, ALCAT1 lacks a preference for linoleic acid as a substrate [ 20 , 21 ]. Consequently, CL remodeling by ALCAT1 with very-long-chain fatty acids, such as docosahexaenoic acid (DHA) and arachidonic acid, leads to TLCL deficiency, oxidative stress, and mitochondrial dysfunction, which is implicated in the pathogenesis of various age-related diseases [ 17 , 18 , 37 , 38 , 39 ].…”

“…CL is a cone-shaped non-bilayer phospholipid predominantly localized in the curved membrane sites of mitochondrial cristae, where it is believed to stabilize respiratory chain complexes ( Figure 3 ) [ 41 , 42 , 43 ]. Consequently, CL depletion in age-related diseases leads to mitochondrial fragmentation, oxidative stress, defective oxidative respiration, and mtDNA release to the cytosol ( Figure 3 ) [ 17 , 18 , 37 , 38 , 44 , 45 , 46 , 47 ]. CL is particularly sensitive to the oxidation of its double bonds by ROS due to its exclusive location near the site of ROS production in the inner mitochondrial membrane [ 48 ].…”

“…Moreover, ALCAT1 expression is upregulated by oxidative stress associated with age-related diseases, which is implicated in the mitochondrial etiology of various age-related diseases in mice. Accordingly, the overexpression of ALCAT1 causes severe oxidative stress, mitochondrial swelling, and defective oxidative phosphorylation, both in metabolic cell lines and in multiple mouse models of age-related metabolic diseases [ 17 , 18 , 47 ]. Consequently, the targeted deletion of the ALCAT1 gene in mice not only prevented mitochondrial dysfunction, but also the development of obesity, T2DM, fatty liver disease, Parkinson’s disease, and cardiomyopathy [ 18 , 38 , 47 , 63 ].…”

“…CL is a polyglycerophospholipid exclusively localized in the mitochondria, where it regulates membrane structure, oxidative phosphorylation, mtDNA biogenesis, fusion, fission, and mitophagy in eukaryotic cells [ 10 , 11 , 12 , 13 , 14 ]. This role is mediated in part by the acyl composition of its four side chains, which are dominated by linoleic acid in insulin-sensitive tissues [ 15 , 16 , 17 , 18 ]. This unique acyl composition is not derived from the de novo synthesis of CL but rather from a remodeling process that involves phospholipases and acyltransferases/transacylases [ 19 , 20 , 21 ].…”