MICU1 Controls Both the Threshold and Cooperative Activation of the Mitochondrial Ca2+ Uniporter

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 [Ca2+](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 [Ca2+](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.