Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo.
Gleeson, Thomas P
von Stockum, Sophia
Hewitt, Victoria L
Lee, Juliette J
Elsevier (Cell Press)
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Tufi, R., Gleeson, T. P., von Stockum, S., Hewitt, V. L., Lee, J. J., Terriente-Felix, A., Sanchez-Martinez, A., et al. (2019). Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo.. Cell Reports, 27 (5), 1541-1550.e5. https://doi.org/10.1016/j.celrep.2019.04.033
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.
Drosophila, EMRE, MCU, MICU1, MICU3, calcium, genetic interaction, genetics, mitochondria
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).
European Commission FP7 ERC Starting Independent Researcher Grant (SIRG) (309742)
External DOI: https://doi.org/10.1016/j.celrep.2019.04.033
This record's URL: https://www.repository.cam.ac.uk/handle/1810/296800
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/