Abstract
| Original language | English |
|---|---|
| Journal | EMBO Reports |
| Volume | 19 |
| Issue number | 4 |
| Publication status | Published - 2018 |
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Keywords
- functional screens
- metabolism
- mitochondria
- Zc3h10
- genomic DNA
- glucose
- regulator protein
- triacylglycerol
- unclassified drug
- Zinc finger CCCH type containing 10
- aged
- animal experiment
- animal tissue
- Article
- body mass
- cell differentiation
- cell isolation
- citric acid cycle
- controlled study
- embryo
- fat mass
- female
- gene overexpression
- glucose blood level
- homozygote
- human
- human cell
- human tissue
- loss of function mutation
- male
- mitochondrial biogenesis
- mitochondrion
- mouse
- myoblast
- myotube
- nonhuman
- oxygen consumption
- peripheral blood mononuclear cell
- priority journal
- protein depletion
- protein expression
- protein function
- protein subunit
- respiratory chain
- triacylglycerol blood level
- upregulation
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Zc3h10 is a novel mitochondrial regulator. / 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.; De Fabiani, E.; Mitro, N.
In: EMBO Reports, Vol. 19, No. 4, 2018.Research output: Contribution to journal › Article
}
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 -