DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fissionproteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexiaand chemotherapy-induced muscle wasting. However, whether mitochondrial fissionis essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynaminrelated protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Responsewhile the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling.