MICU1 Is an Essential Gatekeeper for MCU-Mediated Mitochondrial Ca2+ Uptake that Regulates Cell Survival

• Published in: Cell Vol. 151; no. 3; pp. 630 - 644
• Main Authors: Mallilankaraman, Karthik, Doonan, Patrick, Cárdenas, César, Chandramoorthy, Harish C., Müller, Marioly, Miller, Russell, Hoffman, Nicholas E., Gandhirajan, Rajesh Kumar, Molgó, Jordi, Birnbaum, Morris J., Rothberg, Brad S., Mak, Don-On Daniel, Foskett, J. Kevin, Madesh, Muniswamy
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 26.10.2012
• Subjects: apoptosis; calcium; calcium channels; cell viability; electron transport chain; membranes; mitochondria; reactive oxygen species; respiratory chain; stress
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.10.011

Mitochondrial Ca2+ (Ca2+m) uptake is mediated by an inner membrane Ca2+ channel called the uniporter. Ca2+ uptake is driven by the considerable voltage present across the inner membrane (ΔΨm) generated by proton pumping by the respiratory chain. Mitochondrial matrix Ca2+ concentration is maintained five to six orders of magnitude lower than its equilibrium level, but the molecular mechanisms for how this is achieved are not clear. Here, we demonstrate that the mitochondrial protein MICU1 is required to preserve normal [Ca2+]m under basal conditions. In its absence, mitochondria become constitutively loaded with Ca2+, triggering excessive reactive oxygen species generation and sensitivity to apoptotic stress. MICU1 interacts with the uniporter pore-forming subunit MCU and sets a Ca2+ threshold for Ca2+m uptake without affecting the kinetic properties of MCU-mediated Ca2+ uptake. Thus, MICU1 is a gatekeeper of MCU-mediated Ca2+m uptake that is essential to prevent [Ca2+]m overload and associated stress. [Display omitted] ▸ MICU1 inhibits the mitochondrial Ca2+ channel MCU under resting conditions ▸ MICU1 sets a cytoplasmic Ca2+ concentration threshold for mitochondrial Ca2+ uptake ▸ Loss of MICU1 results in mitochondrial Ca2+ overload ▸ Mitochondrial Ca2+ overload causes excessive ROS production and cell stress MICU1 puts the brakes on mitochondrial Ca2+ uptake by the mitochondria through its interactions with the uniporter MCU. Voltage across the mitochondrial membrane is coupled to Ca2+ uptake and is large enough that, in the absence of MICU1, mitochondria become overloaded and sensitive to apoptosis.