Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca².

Abstract

Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na⁺/Ca²⁺ exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65 as indispensable for neuronal function. Additionally, skeletal muscle-specific knockout produced adult-onset myopathy preceded by elevated mitochondrial Ca²⁺. Consistently, TMEM65 ablation caused loss of Na⁺-dependent mitochondrial Ca²⁺ export. Notably, blocking mitochondrial Ca²⁺ entry by mitochondrial calcium uniporter (MCU) knockout rescued the early lethality of whole-body Tmem65 ablation, extending lifespan from ~3 weeks to >1 year. These data reveal an essential physiological role for TMEM65 and suggest that modulating mitochondrial Ca²⁺ may offer therapeutic value for TMEM65 misexpression and other mitochondrial diseases associated with Ca²⁺ overload.