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

View ORCID ProfilePaula Gutiérrez-Pérez, Emilio M. Santillán, Thomas Lendl, View ORCID ProfileAnna Schrempf, View ORCID ProfileThomas L. Steinacker, Mila Asparuhova, Marlene Brandstetter, View ORCID ProfileDavid Haselbach, View ORCID ProfileLuisa Cochella
doi: https://doi.org/10.1101/2020.08.31.275644
Paula Gutiérrez-Pérez
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC). 1030 Vienna, Austria
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Emilio M. Santillán
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC). 1030 Vienna, Austria
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Thomas Lendl
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC). 1030 Vienna, Austria
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Anna Schrempf
2Research Center for Molecular Medicine of the Austrian Academy of Sciences. 1090 Vienna, Austria
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Thomas L. Steinacker
3Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
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Mila Asparuhova
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC). 1030 Vienna, Austria
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Marlene Brandstetter
4Electron Microscopy Facility, Vienna BioCenter Core Facilities GmbH, Vienna, Austria
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David Haselbach
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC). 1030 Vienna, Austria
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Luisa Cochella
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC). 1030 Vienna, Austria
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  • ORCID record for Luisa Cochella
  • For correspondence: cochella@imp.ac.at
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Abstract

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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 01, 2020.
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A deeply conserved miR-1 dependent regulon supports muscle cell physiology
Paula Gutiérrez-Pérez, Emilio M. Santillán, Thomas Lendl, Anna Schrempf, Thomas L. Steinacker, Mila Asparuhova, Marlene Brandstetter, David Haselbach, Luisa Cochella
bioRxiv 2020.08.31.275644; doi: https://doi.org/10.1101/2020.08.31.275644
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A deeply conserved miR-1 dependent regulon supports muscle cell physiology
Paula Gutiérrez-Pérez, Emilio M. Santillán, Thomas Lendl, Anna Schrempf, Thomas L. Steinacker, Mila Asparuhova, Marlene Brandstetter, David Haselbach, Luisa Cochella
bioRxiv 2020.08.31.275644; doi: https://doi.org/10.1101/2020.08.31.275644

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