Regulation of Cardiolipin Remodeling in Human Lymphoblasts

Abstract

BackgroundBarth Syndrome (BTHS) is a rare X‐linked genetic disorder caused by mutations in the TAZ gene. The TAZ gene product, tafazzin, is responsible for remodeling Cardiolipin (CL) with the necessary acyl species. TAZ mutations can result in cardiomyopathy. Monolysocardiolipin acyltransferase‐1 (MLCL AT‐1) is another enzyme capable of CL remodeling.ObjectiveTo examine if MLCL AT‐1 complements tafazzin in the remodeling of CL.MethodsLymphoblasts from normal or BTHS patients were transfected with TAZ and/or MLCL AT‐1 RNAi or an MLCL AT‐1 carrying plasmid. TAZ and MLCL AT‐1 gene expression were analyzed. Other analyses included measuring CL mass, MLCL AT‐1 enzyme activity and radiolabelling studies. Our studies also include using BN PAGE to analyse mitochondrial complexes in normal and BTHS lymphoblasts.ResultsMLCL AT‐1 gene expression increased when TAZ was knocked down. Expression of MLCL AT‐1 elevated CL levels, increased [1‐14C] Linoleic acid incorporation into CL and raised MLCL AT‐1 enzyme activity in normal and BTHS cells in which TAZ was knocked down. The double knockdown results are not lower than TAZ knockdown alone. Results show that MLCL AT‐1 over‐expression is able to elevate mitochondrial complex I formation in BTHS lymphoblasts.ConclusionMLCL AT‐1 over‐expression may serve as a potential therapeutic approach to treat BTHS.Funding:CIHR, Barth Syndrome Foundations of USA and Canada