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Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Tufi, Roberta 
Gleeson, Thomas P 
von Stockum, Sophia 
Hewitt, Victoria L 
Lee, Juliette J 

Abstract

Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmentally lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data reveal the interplay among components of the mitochondrial Ca2+ uniporter and shed light on their physiological requirements in vivo.

Description

Keywords

Drosophila, EMRE, MCU, MICU1, MICU3, calcium, genetic interaction, genetics, mitochondria

Journal Title

Cell Reports

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

27

Publisher

Elsevier (Cell Press)
Sponsorship
European Research Council (309742)
Medical Research Council (MC_UP_1501/1)
Medical Research Council (MC_UU_00015/6)
Medical Research Council (MC_UU_00015/4)
MRC (1659327)
MRC (1659327)
Medical Research Council (MC_UU_00015/7)
This work is supported by MRC core funding (MC_UU_00015/4, MC-A070-5PSB0, and MC_UU_00015/6) and an ERC starting grant (DYNAMITO; 309742) to A.J.W., as well as by the Italian Ministry of Health “Ricerca Finalizzata” (GR-2011-02351151) to E.Z. T.P.G. and J.J.L. are supported by MRC studentships awarded via the MRC MBU. V.L.H. was funded by an EMBO Long-Term Fellowship (ALTF 740-2015) co-funded by the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409).
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