Mitochondrial Ca(2+) uptake through the Ca(2+) 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 Ca(2+)-sensing regulators (MICUs) and pore unit (MCU) of the uniporter. Low MICU1:MCU protein ratio lowered the [Ca(2+)] threshold for Ca(2+) 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 Ca(2+) uptake phenotype and cardiac contractile dysfunction. Thus, the proportion of MICU1-free and MICU1-associated MCU controls these tissue-specific uniporter phenotypes and downstream Ca(2+) tuning of oxidative metabolism.
Recommended CitationPaillard, Melanie; Csordás, György; Szanda, Gergö; Golenár, Tünde; Debattisti, Valentina; Bartok, Adam; Wang, Nadan; Moffat, Cynthia; Seifert, Erin L.; Spät, András; and Hajnóczky, György, "Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca(2+) Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU." (2017). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 218.
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