MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter

György Csordás, Tünde Golenár, Erin L. Seifert, Kimberli J. Kamer, Yasemin Sancak, Fabiana Perocchi, Cynthia Moffat, David Weaver, Sergio De la Fuente, Roman Bogorad, Victor Koteliansky, Jeffrey Adijanto, Vamsi K. Mootha, György Hajnóczky

Research output: Contribution to journalArticlepeer-review

374 Scopus citations

Abstract

Mitochondrial Ca2+ uptake via the uniporter is central to cell metabolism, signaling, and survival. Recent studies identified MCU as the uniporter's likely pore and MICU1, an EF-hand protein, as its critical regulator. How this complex decodes dynamic cytoplasmic [Ca2+] ([Ca2+]c) signals, to tune out small [Ca 2+]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca2+ accumulation during small [Ca2+] c elevations but an attenuated response to agonist-induced [Ca 2+]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca2+]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca2+ binding, yet cells show impaired oxidative metabolism and sensitization to Ca2+ overload. Collectively, the data indicate that MICU1 senses the [Ca2+] c to establish the uniporter's threshold and gain, thereby allowing mitochondria to properly decode different inputs.

Original languageEnglish
Pages (from-to)976-987
Number of pages12
JournalCell Metabolism
Volume17
Issue number6
DOIs
StatePublished - 4 Jun 2013
Externally publishedYes

Fingerprint

Dive into the research topics of 'MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter'. Together they form a unique fingerprint.

Cite this