Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU

Melanie Paillard, György Csordás, Gergö Szanda, Tünde Golenár, Valentina Debattisti, Adam Bartok, Nadan Wang, Cynthia Moffat, Erin L. Seifert, András Spät, György Hajnóczky

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62 Citations (Scopus)

Abstract

Mitochondrial Ca2+ uptake through the Ca2+ uniporter supports cell functions, including oxidative metabolism, while meeting tissue-specific calcium signaling patterns and energy needs. The molecular mechanisms underlying tissue-specific control of the uniporter are unknown. Here, we investigated a possible role for tissue-specific stoichiometry between the Ca2+-sensing regulators (MICUs) and pore unit (MCU) of the uniporter. Low MICU1:MCU protein ratio lowered the [Ca2+] threshold for Ca2+ uptake and activation of oxidative metabolism but decreased the cooperativity of uniporter activation in heart and skeletal muscle compared to liver. In MICU1-overexpressing cells, MICU1 was pulled down by MCU proportionally to MICU1 overexpression, suggesting that MICU1:MCU protein ratio directly reflected their association. Overexpressing MICU1 in the heart increased MICU1:MCU ratio, leading to liver-like mitochondrial Ca2+ uptake phenotype and cardiac contractile dysfunction. Thus, the proportion of MICU1-free and MICU1-associated MCU controls these tissue-specific uniporter phenotypes and downstream Ca2+ tuning of oxidative metabolism.

Original languageEnglish
Pages (from-to)2291-2300
Number of pages10
JournalCell Reports
Volume18
Issue number10
DOIs
Publication statusPublished - Mar 7 2017

Keywords

  • calcium oscillations
  • calcium uniporter
  • signal decoding

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Paillard, M., Csordás, G., Szanda, G., Golenár, T., Debattisti, V., Bartok, A., Wang, N., Moffat, C., Seifert, E. L., Spät, A., & Hajnóczky, G. (2017). Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU. Cell Reports, 18(10), 2291-2300. https://doi.org/10.1016/j.celrep.2017.02.032