Elamipretide Improves Mitochondrial Function in Mitochondrial Trifunctional Protein‐Deficient Mice and Human Fibroblasts

作者：Eduardo Vieira Neto, M. Wang, Austin J. Szuminsky, L. Ferraro, Shakuntala Basu, Xuejun Zhao, Anuradha Karunanidhi, Yu Wang, Jerry Vockley · 发表于：Journal of Inherited Metabolic Disease · 年份：2026 · DOI：10.1002/jimd.70132 · 被引用次数：2 · 研究领域：Metabolism and Genetic Disorders、Mitochondrial Function and Pathology、Adipose Tissue and Metabolism

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 mitochondria...