The mitochondrial calcium uniporter (MCU): molecular identity and physiological roles

Abstract

The direct measurement of mitochondrial [Ca(2+)] with highly specific probes demonstrated that major swings in organellar [Ca(2+)] parallel the changes occurring in the cytosol and regulate processes as diverse as aerobic metabolism and cell death by necrosis and apoptosis. Despite great biological relevance, insight was limited by the complete lack of molecular understanding. The situation has changed, and new perspectives have emerged following the very recent identification of the mitochondrial Ca(2+) uniporter, the channel allowing rapid Ca(2+) accumulation across the inner mitochondrial membrane.

FIGURE 1.

A, schematic representation (upper) and immunolocalization (lower) of the mitochondrial aequorin (mtAEQ) probe (showing correct targeting to mitochondria); HA, haemagglutinin epitope. B, [Ca²⁺]_m (blue traces) and [Ca²⁺]_c (red traces) measurements in HeLa cells upon treatment with 100 μm histamine in the absence (left panel) and presence (right panel) of the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). cytAEQ, cytosolic aequorin.

FIGURE 2.

Pleiotropic roles of mitochondrial Ca²⁺ homeostasis. PDH, pyruvate dehydrogenase; IDH, isocitrate dehydrogenase; αKGDH, α-ketoglutarate dehydrogenase.

FIGURE 3.

Schematic representation of the essential molecular components of mitochondrial Ca²⁺ homeostasis: the electron transport chain complex, building up the electrical driving force for accumulation (ΔΨ), MCU, and the mNCX and mHCX exchangers. cyt, cytochrome c; IMS, intermembrane space.

FIGURE 4.

Strategy for identifying MCU within the MitoCarta database. TMDs, transmembrane domains.