MICU1 is an essential gatekeeper for mcu-mediated mitochondrial Ca 2+ uptake that regulates cell survival

Karthik Mallilankaraman, Patrick Doonan, César Cárdenas, Harish C. Chandramoorthy, Marioly Müller, Russell Miller, Nicholas E. Hoffman, Rajesh Kumar Gandhirajan, Jordi Molgó, Morris J. Birnbaum, Brad S. Rothberg, Don On Daniel Mak, J. Kevin Foskett, Muniswamy Madesh

Research output: Contribution to journalArticle

334 Scopus citations

Abstract

Mitochondrial Ca2+ (Ca2+m) uptake is mediated by an inner membrane Ca2+ channel called the uniporter. Ca2+ uptake is driven by the considerable voltage present across the inner membrane (ΔΨm) generated by proton pumping by the respiratory chain. Mitochondrial matrix Ca2+ concentration is maintained five to six orders of magnitude lower than its equilibrium level, but the molecular mechanisms for how this is achieved are not clear. Here, we demonstrate that the mitochondrial protein MICU1 is required to preserve normal [Ca2+]m under basal conditions. In its absence, mitochondria become constitutively loaded with Ca2+, triggering excessive reactive oxygen species generation and sensitivity to apoptotic stress. MICU1 interacts with the uniporter pore-forming subunit MCU and sets a Ca2+ threshold for Ca2+m uptake without affecting the kinetic properties of MCU-mediated Ca2+ uptake. Thus, MICU1 is a gatekeeper of MCU-mediated Ca2+m uptake that is essential to prevent [Ca2+]m overload and associated stress.

Original languageEnglish (US)
Pages (from-to)630-644
Number of pages15
JournalCell
Volume151
Issue number3
DOIs
StatePublished - Oct 26 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mallilankaraman, K., Doonan, P., Cárdenas, C., Chandramoorthy, H. C., Müller, M., Miller, R., Hoffman, N. E., Gandhirajan, R. K., Molgó, J., Birnbaum, M. J., Rothberg, B. S., Mak, D. O. D., Foskett, J. K., & Madesh, M. (2012). MICU1 is an essential gatekeeper for mcu-mediated mitochondrial Ca 2+ uptake that regulates cell survival. Cell, 151(3), 630-644. https://doi.org/10.1016/j.cell.2012.10.011