Human trifunctional protein alpha links cardiolipin remodeling to beta-oxidation.

ABSTRACT: Cardiolipin (CL) is a mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes involved in the generation of ATP. In order to facilitate its role CL must be remodeled with appropriate fatty acids. We previously identified a human monolysocardiolipin acyltransferase activity which remodels CL via acylation of monolysocardiolipin (MLCL) to CL and was identical to the alpha subunit of trifunctional protein (?TFP) lacking the first 227 amino acids. Full length ?TFP is an enzyme that plays a prominent role in mitochondrial ?-oxidation, and in this study we assessed the role, if any, which this metabolic enzyme plays in the remodeling of CL. Purified human recombinant ?TFP exhibited acyl-CoA acyltransferase activity in the acylation of MLCL to CL with linoleoyl-CoA, oleoyl-CoA and palmitoyl-CoA as substrates. Expression of ?TFP increased radioactive linoleate or oleate or palmitate incorporation into CL in HeLa cells. Expression of ?TFP in Barth Syndrome lymphoblasts, which exhibit reduced tetralinoleoyl-CL, elevated linoleoyl-CoA acylation of MLCL to CL in vitro, increased mitochondrial respiratory Complex proteins and increased linoleate-containing species of CL. Knock down of ?TFP in Barth Syndrome lymphoblasts resulted in greater accumulation of MLCL than those with normal ?TFP levels. The results clearly indicate that the human ?TFP exhibits MLCL acyltransferase activity for the resynthesis of CL from MLCL and directly links an enzyme of mitochondrial ?-oxidation to CL remodeling.

SUBMITTER: Taylor WA 

PROVIDER: S-EPMC3494688 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature