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

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2026年4月14日

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Yingfan Zhang,
Hailey A. Parry,
Laura Reyes,
Alex Shamoun,
Junhui Sun,
Chengyu Liu,
Danielle Springer,
Audrey Noguchi,
Sachiko Nakamori,
Angel M. Aponte,
Jeeva Munasinghe,
Raul Covian,
Elizabeth Murphy,
Brian Glancy

摘要

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.

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

摘要

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