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Τρίτη 7 Μαρτίου 2017

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

Publication date: 7 March 2017
Source:Cell Reports, Volume 18, Issue 10
Author(s): Melanie Paillard, György Csordás, Gergö Szanda, Tünde Golenár, Valentina Debattisti, Adam Bartok, Nadan Wang, Cynthia Moffat, Erin L. Seifert, András Spät, György Hajnóczky
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.

Graphical abstract

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Teaser

Paillard et al. report that the relative abundance of the pore-forming protein of the mitochondrial Ca2+ uniporter (MCU) and its Ca2+-sensing regulator (MICU1) define the proportion of MCU complexes with or without MICU1. This ratio is central to programming tissue-specific mitochondrial Ca2+ uptake phenotypes in the heart and liver.


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