Mitochondrial Calcium Uniporter

The mitochondrial Ca²⁺ uniporter (MCU) is a transmembrane protein that modulates mitochondrial Ca²⁺ uptake. Sequestration of Ca²⁺ is important for the processes of oxidative phosphorylation and induction of the mitochondrial permeability transition (MPT).

The MCU is one of the main mechanisms by which mitochondria can take up Ca²⁺. Ca²⁺ accumulation via MCU is dependent on the calcium concentration gradient between the cytosol and mitochondrial matrix and the membrane potential (Δψ_m) generated by the electron transport chain. The ability of the mitochondria to buffer [Ca²⁺] inside the matrix ([Ca²⁺]_m) must be carefully maintained in order to ensure an appropriate and rapid response to cellular Ca²⁺ signals ([Ca²⁺]_c) through buffering, increasing the cell's energy supply, or triggering apoptosis. Balancing mitochondrial Ca²⁺ is achieved in conjunction with the Na⁺/Ca²⁺ exchanger (NCX), which enables the exchange of calcium for sodium ions. Na⁺ ions are then removed from the matrix by exchange for protons, via the Na⁺/H⁺ exchanger (NHE). If [Ca²⁺]_m reaches critical levels, the mitochondrial permeability transition pore (MPTP) opens for a prolonged period, and programmed cell death results.

Ca²⁺ accumulation in mitochondria is closely linked to oxidative phosphorylation and the production of ATP via the activation of key metabolic enzymes, such as pyruvate dehydrogenase and isocitrate dehydrogenase. It can also stimulate ATP synthase and adenine nucleotide translocase (ANT), which is linked to opening of the MPTP. Consequently, the rise in [Ca²⁺]_m upregulates oxidative phosphorylation. Under pathological conditions however, Ca²⁺ may influence mitochondrial dysfunction; for example, reactive oxygen species (ROS) trigger MPTP opening, an activity that is potentiated by Ca²⁺. Mitochondrial dysfunction has been linked to neuronal damage, such as that observed in Alzheimer's disease. Combined with the role of calcium overload in cell death, the pathological roles of calcium and ROS in this context are of particular interest.

Mitochondrial Calcium Uniporter Gene Data