Zc3h10 controls mitochondrial function coupling iron and cardiolipin homeostasis

Identification: Mitro, Nico


Description

Zc3h10 controls mitochondrial function coupling iron and cardiolipin homeostasis
 
N. Mitro1*, M. Audano1, S. Pedretti1, M. Pelizzola2, T. Bonaldi3, A. L. Catapano1,4, G. D. Norata1,5,6, M. Crestani1, D. Caruso1, E. Saez7, and E. De Fabiani1
1Department of Pharmacological and Biomolecular Sciences, University of Milan (Milan, Italy); 2Center for Genomic Science of IIT@SEMM (Milan, Italy); 3Department of Experimental Oncology, European Institute of Oncology (Milan, Italy); 4IRCSS Multimedica, (Milan, Italy); 5SISA Center Bassini Hospital (Milan, Italy); 6School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, (Perth, Australia); 7Department of Molecular Medicine, The Scripps Research Institute (La Jolla, CA, USA)
*Corresponding author.
 
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. Here, we have applied an integrated approach (genomics, transcriptomics, proteomics, metabolomics, cell-based assays, human genetics) to show that the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) regulates mitochondrial physiology. We show that Zc3h10 is upregulated during physiological mitochondriogenesis such as myoblasts differentiation into myotubes. Zc3h10 overexpression boosts mitochondrial function and promotes myoblasts differentiation. On the other hand, depletion of Zc3h10 results in impaired myoblasts differentiation, mitochondrial dysfunction, reduced expression of electron transport chain (ETC) subunits and blunted Krebs cycle flux. We also show that Zc3h10 is a nuclear RNA binding protein that controls the fate of Slc25a37 and Prelid3a mRNA transcripts, two nuclear-encoded mitochondrial proteins central for iron and cardiolipin homeostasis. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with decreased mitochondrial function, increased body mass index, fat mass, fasting glucose and triglycerides. Cells from Cys105 homozygotes display alterations in Slc25a37 and Prelid3a levels and defects in mitochondrial iron and cardiolipin homeostasis that derive in mitochondrial dysfunction.
 
This work is supported by Cariplo Foundation (grant number 2014-0991) and by European Foundation for the Study of Diabetes (EFSD)/ Lilly European Diabetes Research Programme 2015.

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