Sertraline disrupts ETFDH-mediated mitochondrial fatty acid oxidation and promotes long-chain acylcarnitine accumulation

Emerging clinical evidence suggests that sertraline exposure may be associated with acquired multiple acyl-CoA dehydrogenase deficiency (MADD)-like metabolic abnormalities, but the underlying mechanism remains unclear. Differentiated C2C12 skeletal muscle cells were exposed to sertraline to evaluate acylcarnitine profiles, mitochondrial bioenergetics, and ETF/ETFDH pathway function. ETFDH stability and its functional contribution were investigated using cycloheximide chase, degradation inhibitors, gene knockdown, overexpression, and riboflavin supplementation. Sertraline induced concentration-dependent accumulation of C14-C18 acylcarnitines, impaired fatty acid-supported respiration, reduced ATP production and mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and promoted lipid accumulation. Sertraline reduced ETFDH protein abundance without altering its mRNA levels or mitochondrial content, accelerated ETFDH loss, and preferentially impaired ETF/ETFDH-dependent respiration while largely preserving complex I- and II-linked respiration. ETFDH knockdown reproduced these abnormalities, whereas ETFDH overexpression and riboflavin supplementation partially restored mitochondrial function and reduced acylcarnitine accumulation. These findings suggest that sertraline induces a MADD-like metabolic phenotype associated with reduced ETFDH abundance, altered protein turnover, and impaired ETF/ETFDH-dependent electron transfer. Changes in mitochondrial or cellular protein homeostasis may contribute to ETFDH loss, although the underlying mechanisms require further investigation.