PT - JOURNAL ARTICLE AU - Paula Gutiérrez-Pérez AU - Emilio M. Santillán AU - Thomas Lendl AU - Anna Schrempf AU - Thomas L. Steinacker AU - Mila Asparuhova AU - Marlene Brandstetter AU - David Haselbach AU - Luisa Cochella TI - A deeply conserved miR-1 dependent regulon supports muscle cell physiology AID - 10.1101/2020.08.31.275644 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.08.31.275644 4099 - http://biorxiv.org/content/early/2020/09/01/2020.08.31.275644.short 4100 - http://biorxiv.org/content/early/2020/09/01/2020.08.31.275644.full AB - Muscles are not only essential for force generation but are also key regulators of systemic energy homeostasis1. Both these roles rely heavily on mitochondria and lysosome function as providers of energy and building blocks, but also as metabolic sensors2-4. Perturbations in these organelles or their crosstalk lead to a wide range of pathologies5. 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 targets6. 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 signaling7,8, and of DCT-1/BNIP3, a mitochondrial protein involved in mitophagy and apoptosis9,10, 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.Competing Interest StatementThe authors have declared no competing interest.