Elamipretide Improves Mitochondrial Function in Mitochondrial Trifunctional Protein-Deficient Mice and Human...

Area of Science:

• Biochemistry
• Mitochondrial Biology
• Metabolic Disorders

Background:

• Mitochondrial trifunctional protein (TFP) deficiency impairs long-chain fatty acid beta-oxidation (FAO), leading to severe complications like hypoglycemia and cardiomyopathy.
• Existing treatments improve some symptoms but not peripheral neuropathy or retinopathy, particularly in isolated alpha-TFP (LCHAD) deficiency.
• TFP's role in cardiolipin remodeling is impaired in TFP/LCHAD deficiency, suggesting a novel therapeutic target.

Purpose of the Study:

• To investigate elamipretide's efficacy in improving mitochondrial function and addressing complications in beta-TFP deficient mice and patient-derived fibroblasts.
• To determine if elamipretide's therapeutic effects are mediated by changes in cardiolipin levels or by stabilizing mitochondrial enzyme complexes.

Main Methods:

• Treatment of beta-TFP deficient mice with elamipretide via osmotic minipump, followed by exercise and cold stress challenges.
• Assessment of liver mitochondrial FAO-ETC enzyme activities, cardiolipin content, and composition in treated mice.
• Evaluation of elamipretide's impact on mitochondrial bioenergetics and reactive oxygen species (ROS) in patient-derived fibroblasts.

Main Results:

• Elamipretide significantly improved exercise endurance in beta-TFP deficient mice, though cold tolerance remained unaffected.
• Liver mitochondria from treated male mice showed enhanced FAO-ETC enzyme activities, but cardiolipin levels and composition were unchanged.
• Patient fibroblasts exhibited potential genotype-dependent improvements in mitochondrial bioenergetics and reduced ROS production with elamipretide treatment.

Conclusions:

• Elamipretide enhances mitochondrial function in TFP/LCHAD deficiency by stabilizing FAO enzymes and ETC complexes, independent of cardiolipin remodeling.
• These findings position elamipretide as a promising therapeutic candidate for TFP/LCHAD deficiency, meriting further preclinical investigation.