Abstract
Mitochondrial trifunctional protein (TFP) deficiency is an inherited disorder of long-chain fatty acid β-oxidation (FAO). TFP is a heteromeric enzyme composed of two α and two β-subunits. Despite early detection and dietary treatment, TFP deficiency patients often develop hypoglycemia, rhabdomyolysis, cardiomyopathy, and peripheral neuropathy. Degenerative retinopathy and milder peripheral neuropathy occur in patients with an isolated deficiency of the αTFP subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity. Triheptanoin treatment improves most complications, but not peripheral neuropathy and retinopathy. Notably, TFP also carries a fourth enzymatic function involved in cardiolipin remodeling, which we previously found to be impaired in TFP/LCHAD deficiency. We therefore tested whether elamipretide, a synthetic cardiolipin-binding peptide, could improve mitochondrial function and cardiolipin levels in βTFP-deficient mice and patient-derived fibroblasts. Mice were treated with elamipretide delivered by osmotic minipump and challenged with treadmill exercise or cold stress after fasting. βTFP-deficient mice treated with elamipretide showed improved exercise endurance, but cold tolerance was not altered. Liver mitochondria from male βTFP-deficient mice demonstrated improved FAO-ETC enzyme activities. However, cardiolipin content and composition were unchanged. In patient fibroblasts, elamipretide produced a possible genotype-dependent increase in mitochondrial bioenergetics and a reduction in ROS. These results support a mechanism in which elamipretide stabilizes between FAO enzymes and ETC complexes, thereby improving mitochondrial function independently of changes in cardiolipin levels. Elamipretide thus emerges as a potential therapeutic agent for TFP/LCHAD deficiency, warranting further preclinical studies.