Cardiolipin remodeling: a regulatory hub for modulating cardiolipin metabolism and function

Abstract

Cardiolipin (CL), the signature phospholipid of mitochondria, is involved in a plethora of cellular processes and is crucial for mitochondrial function and architecture. The de novo synthesis of CL in the mitochondria is followed by a unique remodeling process, in which CL undergoes cycles of deacylation and reacylation. Specific fatty acyl composition is acquired during this process, and remodeled CL contains predominantly unsaturated fatty acids. The importance of CL remodeling is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), caused by mutations in tafazzin, which reacylates monolysocardiolipin (MLCL) generated from the deacylation of CL. Just as CL-deficient yeast mutants have been instrumental in elucidating functions of this lipid, the recently characterized CL-phospholipase mutant cld1Δ and the tafazzin mutant taz1Δ are powerful tools to understand the functions of CL remodeling. In this review, we discuss recent advances in understanding the role of CL in mitochondria with specific focus on the enigmatic functions of CL remodeling.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…2016; Ye et al. 2016). In our study, we observed alterations in cardiac cardiolipin fatty‐acid species composition, namely a loss of the symmetric tetralinoleoyl‐CL in favor of more asymmetric cardiolipins with shorter and more saturated chains (Fig.…”

Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function

“…CL is synthesized and remodeled within the mitochondria, but its precursors, phosphatidic acid and CDPdiacylglycerol, are formed primarily on the endoplasmic reticulum and are imported into the mitochondria where phosphatidylglycerol is synthesized ( 28 ). CL synthase then combines phosphatidylglycerol with the phosphatidyl group from a second molecule of CDP-diacylglycerol.…”

“…In Saccharomyces cerevisiae lacking tafazzin, an additional deletion of the CL-specifi c phospholipase, Cld1, prevents the accumulation of MLCL, inhibits CL remodeling, and rescues the mitochondrial respiratory defect, strongly suggesting that the respiratory defect had been due to the accumulation of MLCL and/or the decrease in the total content of CL ( 25 ). In mammalian cells, two additional enzymes, lysocardiolipin acyltransferase 1 (AL-CAT1) and MLCL acyltransferase 1 (MLCL AT-1), can use acyl-CoAs to esterify MLCL ( 28 ). ALCAT1, however, is located on the ER, which would prevent its interaction with most CL ( 30 ), but MLCL AT-1 is present in mitochondria ( 11 ).…”

Cardiolipin metabolism and its causal role in the etiology of the inherited cardiomyopathy Barth syndrome

“…Consistent with the decreased capacity of cells lacking tafazzin function to undergo mitophagy when stressed, a specific role for CL as a mitophagy initiator signal has emerged (Chu et al, 2014;Chu et al, 2013;Galbraith, 2014;Li et al, 2015;Ye et al, 2014b;Zhu et al, 2013). Recently, in rat cortical neurons, CL was shown to redistribute from the MIM to the MOM and then specifically bind to microtubule-associated protein 1 light chain 3 (MAP1LC3/LC3) upon mitophagy induction (Chu et al, 2013).…”