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Loss of TMEM65 in mice causes mitochondrial disease mediated by mitochondrial Ca2
Yingfan Zhang1, Hailey A Parry1, Laura Reyes2
1National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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.
Insights
Transmembrane protein 65 (TMEM65) is crucial for neuronal function and preventing mitochondrial calcium overload. Its absence causes severe neurological and muscle disorders, but blocking calcium entry can extend lifespan.
Area of Science:
- Mitochondrial Biology
- Neuroscience
- Muscle Physiology
Background:
- Transmembrane protein 65 (TMEM65) depletion is linked to severe mitochondrial encephalomyopathy.
- In vitro studies suggest TMEM65 functions as a mitochondrial Na+/Ca2+ exchanger.
Purpose of the Study:
- To investigate the in vivo role of TMEM65 in neuromuscular tissues using conditional knockout mice.
- To elucidate the physiological function of TMEM65 in neuronal and skeletal muscle health.
Main Methods:
- Generated conditional Tmem65 knockout mouse models (whole-body, nervous system-specific, skeletal muscle-specific).
- Analyzed phenotypes including growth, survival, seizures, and myopathy.
- Assessed mitochondrial Ca2+ levels and Na+-dependent Ca2+ export.
- Utilized mitochondrial calcium uniporter (MCU) knockout to investigate rescue effects.
Main Results:
- Whole-body and nervous system-specific Tmem65 knockouts showed growth retardation and premature death (~3 weeks) due to impaired neuronal function.
- Skeletal muscle-specific Tmem65 knockout resulted in adult-onset myopathy with elevated mitochondrial Ca2+ and impaired Na+-dependent Ca2+ export.
- Mitochondrial calcium uniporter (MCU) knockout rescued the lethality of Tmem65 ablation, significantly extending lifespan.
Conclusions:
- TMEM65 is essential for maintaining neuronal function and preventing mitochondrial Ca2+ overload in vivo.
- Dysfunctional TMEM65 leads to severe neuromuscular disorders, highlighting its physiological importance.
- Targeting mitochondrial Ca2+ transport presents a potential therapeutic strategy for TMEM65-related disorders and other mitochondrial diseases.
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