Zc3h10 is a novel mitochondrial regulator

TY - JOUR

T1 - Zc3h10 is a novel mitochondrial regulator

AU - Audano, M.

AU - Pedretti, S.

AU - Cermenati, G.

AU - Brioschi, E.

AU - Diaferia, G.R.

AU - Ghisletti, S.

AU - Cuomo, A.

AU - Bonaldi, T.

AU - Salerno, F.

AU - Mora, M.

AU - Grigore, L.

AU - Garlaschelli, K.

AU - Baragetti, A.

AU - Bonacina, F.

AU - Catapano, A.L.

AU - Norata, G.D.

AU - Crestani, M.

AU - Caruso, D.

AU - Saez, E.

AU - De Fabiani, E.

AU - Mitro, N.

N1 - Export Date: 5 February 2019 CODEN: ERMEA Correspondence Address: De Fabiani, E.; DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di MilanoItaly; email: emma.defabiani@unimi.it Chemicals/CAS: glucose, 50-99-7, 84778-64-3 Funding details: Ministero della Salute, GR-2011-02346974, 2016-WI218287, GR-2013-02355011 Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC Funding details: Eli Lilly and Company Funding details: College of Natural Resources, University of California Berkeley, CNR Funding details: European Foundation for the Study of Diabetes, EFSD Funding details: Fondazione Cariplo, 2015-0524, 2016-0852, 2014-0991, 2015-0564 Funding details: RF-GR2011 Funding text 1: We thank F. Giavarini for his valuable help with HPLC and mass spectrometry. We also thank A. Maggi for critically reading the manuscript and for her helpful comments and all the members of the laboratory for valuable discussion. We are in debt with Ms. E. Desiderio Pinto for administrative assistance. T. Bonaldi is supported by grants from the Italian Association for Cancer Research (AIRC), the Italian Ministry of Health (RF-GR2011), and the Epigen Flagship project grant (CNR). This work is supported by Ministero della Salute GR-2011-02346974 to GDN and GR-2013-02355011 to FB; Aspire Cardiovascular Grant 2016-WI218287 to GDN, The Giovanni Armenise Harvard-Foundation Career Development Grant, Cariplo Foundation (grant number 2014-0991 to NM, 2015-0524 and 2015-0564 to ALC, 2016-0852 to GDN), European Foundation for the Study of Diabetes (EFSD)/Lilly European Diabetes Research Programme 2015 to N.M. This research was supported by grants from MIUR Progetto Eccellenza. 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PY - 2018

Y1 - 2018

N2 - 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. © 2018 The Authors

AB - 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. © 2018 The Authors

KW - functional screens

KW - metabolism

KW - mitochondria

KW - Zc3h10

KW - genomic DNA

KW - glucose

KW - regulator protein

KW - triacylglycerol

KW - unclassified drug

KW - Zinc finger CCCH type containing 10

KW - aged

KW - animal experiment

KW - animal tissue

KW - Article

KW - body mass

KW - cell differentiation

KW - cell isolation

KW - citric acid cycle

KW - controlled study

KW - embryo

KW - fat mass

KW - female

KW - gene overexpression

KW - glucose blood level

KW - homozygote

KW - human

KW - human cell

KW - human tissue

KW - loss of function mutation

KW - male

KW - mitochondrial biogenesis

KW - mitochondrion

KW - mouse

KW - myoblast

KW - myotube

KW - nonhuman

KW - oxygen consumption

KW - peripheral blood mononuclear cell

KW - priority journal

KW - protein depletion

KW - protein expression

KW - protein function

KW - protein subunit

KW - respiratory chain

KW - triacylglycerol blood level

KW - upregulation

M3 - Article

VL - 19

JO - EMBO Reports

JF - EMBO Reports

SN - 1469-221X

IS - 4

ER -