Comprehensive Genetic Characterisation of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements in Vivo
Gleeson, Thomas P
von Stockum, Sophia
Hewitt, Victoria L
Lee, Juliette J
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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 Characterisation of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements in Vivo. Cell Reports, 27 (5), 1541-1550.e5. https://doi.org/10.2139/ssrn.3305558
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 characterisation 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 developmental 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 interrogates the interplay between components of the mitochondrial Ca2+ uniporter, and sheds light on their physiological requirements in vivo.
This work is supported by MRC core funding (MC_UU_00015/4, MC-A070-5PSB0 and MC_UU_00015/6) and ERC Starting grant (DYNAMITO; 309742) to A.J.W., and 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). Stocks were obtained from the Bloomington Drosophila Stock Center which is supported by grant NIH P40OD018537, and material was obtained from the Drosophila Genomics Resource Center, which is supported by NIH grant 2P40OD010949.
European Commission FP7 ERC Starting Independent Researcher Grant (SIRG) (309742)
External DOI: https://doi.org/10.2139/ssrn.3305558
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292693
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/