A deeply conserved miR-1 dependent regulon supports muscle cell physiology

Muscles are not only essential for force generation but are also key regulators of systemic energy homeostasis 1 . Both these roles rely heavily on mitochondria and lysosome function as providers of energy and building blocks, but also as metabolic sensors 2-4 . Perturbations in these organelles or their crosstalk lead to a wide range of pathologies 5 . Here, we uncover a deeply conserved regulon of mitochondria and lysosome homeostasis under control of the muscle-specific microRNA miR-1. Animals lacking miR-1 display a diverse range of muscle cell defects that have been attributed to numerous different targets 6 . Guided by the striking conservation of miR-1 and some of its predicted targets, we identified a set of direct targets that can explain the pleiotropic function of miR-1. miR-1-mediated repression of multiple subunits of the vacuolar ATPase (V-ATPase) complex, a key player in the acidification of internal compartments and a hub for metabolic signaling 7,8 , and of DCT-1/BNIP3, a mitochondrial protein involved in mitophagy and apoptosis 9,10 , accounts for the function of this miRNA in C. elegans . Surprisingly, although multiple V-ATPase subunits are upregulated in the absence of miR-1, this causes a loss-of-function of V-ATPase due to altered levels or stoichiometry, which negatively impact complex assembly. Finally, we demonstrate the conservation of the functional relationship between miR-1 and the V-ATPase complex in Drosophila .