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][1]. Both these roles rely heavily on mitochondria and lysosome function as providers of energy and building blocks, but also as metabolic sensors[2][2]-[4][3]. Perturbations in these organelles or their crosstalk lead to a wide range of pathologies[5][4]. 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][5]. 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][6],[8][7], and of DCT-1/BNIP3, a mitochondrial protein involved in mitophagy and apoptosis[9][8],[10][9], 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 . ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-4 [4]: #ref-5 [5]: #ref-6 [6]: #ref-7 [7]: #ref-8 [8]: #ref-9 [9]: #ref-10