Journal
CELL REPORTS
Volume 27, Issue 5, Pages 1541-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.04.033
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Funding
- MRC [MC_ UU_ 00015/4, MC-A070-5PSB0, MC_UU_00015/6]
- ERC [309742]
- Italian Ministry of Health Ricerca Finalizzata'' [GR-2011-02351151]
- MRC studentships via the MRC MBU
- EMBO Long-Term Fellowship - European Commission FP7 (Marie Curie Actions, LTFCOFUND2013) [ALTF 740-2015, GA-2013-609409]
- NIH [P40OD018537, 2P40OD010949]
- MRC [MC_UP_1501/1, MC_UU_00015/6, MC_UU_00015/4] Funding Source: UKRI
- European Research Council (ERC) [309742] Funding Source: European Research Council (ERC)
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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.
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