Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency

• Published in: JCI insight Vol. 9; no. 17
• Main Authors: Vieira Neto, Eduardo, Wang, Meicheng, Szuminsky, Austin J, Ferraro, Lethicia, Koppes, Erik, Wang, Yudong, Van't Land, Clinton, Mohsen, Al-Walid, Zanatta, Geancarlo, El-Gharbawy, Areeg H, Anthonymuthu, Tamil S, Tyurina, Yulia Y, Tyurin, Vladimir A, Kagan, Valerian, Bayır, Hülya, Vockley, Jerry
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 10-09-2024
• Subjects: Animals; Cardiolipins - metabolism; Cardiomyopathies; Disease Models, Animal; Energy Metabolism - genetics; Fibroblasts - metabolism; Humans; Lipid Metabolism, Inborn Errors - genetics; Lipid Metabolism, Inborn Errors - metabolism; Lipid Metabolism, Inborn Errors - pathology; Lysophospholipids; Male; Mice; Mitochondria - metabolism; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; Mitochondrial Myopathies - pathology; Mitochondrial Trifunctional Protein - deficiency; Mitochondrial Trifunctional Protein - genetics; Mitochondrial Trifunctional Protein - metabolism; Mitochondrial Trifunctional Protein, alpha Subunit - genetics; Mitochondrial Trifunctional Protein, alpha Subunit - metabolism; Mitochondrial Trifunctional Protein, beta Subunit - genetics; Mitochondrial Trifunctional Protein, beta Subunit - metabolism; Mutation; Nervous System Diseases; Oxygen Consumption; Rhabdomyolysis - genetics; Rhabdomyolysis - metabolism; Rhabdomyolysis - pathology; Fatty acid oxidation; Genetics; Mitochondria; Intermediary metabolism; Metabolism
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.176887

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.