Zc3h10 is a novel mitochondrial regulator. (5th March 2018)

• Record Type: Journal Article
• Authors: Audano, Matteo; Pedretti, Silvia; Cermenati, Gaia; Brioschi, Elisabetta; Diaferia, Giuseppe Riccardo; Ghisletti, Serena; Cuomo, Alessandro; Bonaldi, Tiziana; Salerno, Franco; Mora, Marina; Grigore, Liliana; Garlaschelli, Katia; Baragetti, Andrea; Bonacina, Fabrizia; Catapano, Alberico Luigi; Norata, Giuseppe Danilo; Crestani, Maurizio; Caruso, Donatella; Saez, Enrique; De Fabiani, Emma; Mitro, Nico
• Is Part Of: EMBO reports. Volume 19:Number 4(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-03-05
• Subjects: functional screens -- metabolism -- mitochondria -- Zc3h10; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201745531
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: Genome‐wide functional screens coupled to integrated omic approaches identify Zinc finger CCCH‐type containing 10 (Zc3h10) as a new regulator of mitochondrial biology. Zc3h10 silencing in vitro and mutation in vivo are associated with impaired mitochondrial function. Genomic screens identify the poorly characterized Zc3h10 as a novel mitochondrial regulator. Zc3h10 silencing in vitro impairs mitochondrial oxidative capacity in myoblasts and delays myogenesis. Cys105 mutation leads to Zc3h10 loss of function and is associated with compromised metabolic trait and mitochondrial dysfunction in human isolated PBMCs. Abstract : Genome‐wide functional screens coupled to integrated omic approaches identify Zinc finger CCCH‐type containing 10 (Zc3h10) as a new regulator of mitochondrial biology. Zc3h10 silencing in vitro and mutation in vivo are associated with impaired mitochondrial function.