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

TitleComprehensive Genetic Characterization of Mitochondrial Ca Uniporter Components Reveals Their Different Physiological Requirements In Vivo.
Publication TypeJournal Article
Year of Publication2019
AuthorsTufi, R, Gleeson, TP, von Stockum, S, Hewitt, VL, Lee, JJ, Terriente-Felix, A, Sanchez-Martinez, A, Ziviani, E, Whitworth, AJ
JournalCell Rep
Volume27
Issue5
Pagination1541-1550.e5
Date Published2019 Apr 30
ISSN2211-1247
Abstract

Mitochondrial Ca uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca 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 Ca 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 Ca 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 Ca uniporter and shed light on their physiological requirements in vivo.

DOI10.1016/j.celrep.2019.04.033
Alternate JournalCell Rep
Citation Key10.1016/j.celrep.2019.04.033
PubMed ID31042479
PubMed Central IDPMC6506686
Grant ListP40 OD010949 / OD / NIH HHS / United States
P40 OD018537 / OD / NIH HHS / United States