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 (αTFP) lacking the first 227
amino acids. Full length αTFP is an
enzyme that plays a prominent role in mitochondrial β-oxidation, and in this study we assessed the role, if any, which this metabolic
enzyme plays in the remodeling of CL. Purified human recombinant αTFP exhibited
acyl-CoA acyltransferase activity in the acylation of MLCL to CL with
linoleoyl-CoA,
oleoyl-CoA and
palmitoyl-CoA as substrates. Expression of αTFP increased radioactive
linoleate or
oleate or
palmitate incorporation into CL in HeLa cells. Expression of αTFP 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 αTFP in
Barth Syndrome lymphoblasts resulted in greater accumulation of MLCL than those with normal αTFP levels. The results clearly indicate that the human αTFP exhibits MLCL
acyltransferase activity for the resynthesis of CL from MLCL and directly links an
enzyme of mitochondrial β-oxidation to CL remodeling.