Zc3h10 is a novel mitochondrial regulator

Matteo Audano, Silvia Pedretti, Gaia Cermenati, Elisabetta Brioschi, Giuseppe Riccardo Diaferia, Serena Ghisletti, Alessandro Cuomo, Tiziana Bonaldi, Franco Salerno, Marina Mora, Liliana Grigore, Katia Garlaschelli, Andrea Baragetti, Fabrizia Bonacina, Alberico Luigi Catapano, Giuseppe Danilo Norata, Maurizio Crestani, Donatella Caruso, Enrique Saez, Emma De FabianiNico Mitro

Research output: Contribution to journalArticle

Abstract

Mitochondria are the energy-generating hubs of the cell. In spite of considerable advances, our understanding of the factors that regulate the molecular circuits that govern mitochondrial function remains incomplete. Using a genome-wide functional screen, we identify the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) as regulator of mitochondrial physiology. We show that Zc3h10 is upregulated during physiological mitochondriogenesis as it occurs during the differentiation of myoblasts into myotubes. Zc3h10 overexpression boosts mitochondrial function and promotes myoblast differentiation, while the depletion of Zc3h10 results in impaired myoblast differentiation, mitochondrial dysfunction, reduced expression of electron transport chain (ETC) subunits, and blunted TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with increased body mass index, fat mass, fasting glucose, and triglycerides. Isolated peripheral blood mononuclear cells from individuals homozygotic for Cys105 display reduced oxygen consumption rate, diminished expression of some ETC subunits, and decreased levels of some TCA cycle metabolites, which all together derive in mitochondrial dysfunction. Taken together, our study identifies Zc3h10 as a novel mitochondrial regulator.

Original languageEnglish
Article numbere45531
JournalEMBO Reports
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

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Keywords

  • functional screens
  • metabolism
  • mitochondria
  • Zc3h10

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Audano, M., Pedretti, S., Cermenati, G., Brioschi, E., Diaferia, G. R., Ghisletti, S., Cuomo, A., Bonaldi, T., Salerno, F., Mora, M., Grigore, L., Garlaschelli, K., Baragetti, A., Bonacina, F., Catapano, A. L., Norata, G. D., Crestani, M., Caruso, D., Saez, E., ... Mitro, N. (2018). Zc3h10 is a novel mitochondrial regulator. EMBO Reports, 19(4), [e45531]. https://doi.org/10.15252/embr.201745531