Mitochondrial Ca(2+) 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 [Ca(2+)] ([Ca(2+)]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 Ca(2+) accumulation during small [Ca(2+)]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 [Ca(2+)]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca(2+) binding, yet cells show impaired oxidative metabolism and sensitization to Ca(2+) overload. Collectively, the data indicate that MICU1 senses the [Ca(2+)]c to establish the uniporter's threshold and gain, thereby allowing mitochondria to properly decode different inputs.
Recommended CitationCsordás, György; Golenár, Tünde; Seifert, Erin L; Kamer, Kimberli J; Sancak, Yasemin; Perocchi, Fabiana; Moffat, Cynthia; Weaver, David; de la Fuente Perez, Sergio; Bogorad, Roman; Koteliansky, Victor; Adijanto, Jeffrey; Mootha, Vamsi K; and Hajnóczky, György, "MICU1 Controls Both the Threshold and Cooperative Activation of the Mitochondrial Ca(2+) Uniporter." (2013). Department of Pathology, Anatomy and Cell Biology Faculty Papers. Paper 102.