Ablation of Tmem65 Causes Lethal Mitochondrial Encephalomyopathy in Mouse

Abstract

ABSTRACTDepletion of transmembrane protein 65 (TMEM65) in a patient with a homozygous point mutation in the TMEM65 gene splice site was reported to result in mitochondrial dysfunction and severe encephalomyopathy(1), indicating the clinical importance of TMEM65. However, the function of TMEM65 remains unknown, and the specific subcellular localization of TMEM65 to either the mitochondrial inner membrane or cardiac intercalated disc remains controversial. Here, we generated a Tmem65 reporter mouse as well as whole-body and tissue-specific Tmem65 knockout (KO) mice to investigate the localization and function of TMEM65. We show that TMEM65 is localized to mitochondria in heart, skeletal muscle, and throughout the brain. Both whole-body and nervous system- specific Tmem65 KO resulted in severe growth retardation and sudden death following seizures ∼3 weeks after birth indicating TMEM65 is indispensable for normal brain function. Cardiac-specific Tmem65 KO mice were viable and fertile but had reduced mitochondrial content and cardiac stress response. Skeletal muscle-specific Tmem65 KO led to progressive, adult-onset myopathy manifested by wasting of muscle fibers, upregulation of one-carbon metabolic pathways, and reduced whole-body metabolic efficiency. These results highlight the effectiveness of a Tmem65 KO mouse model to recapitulate and further interrogate the clinical phenotypes associated with a loss of TMEM65.