Mitochondrial Ca2+ uptake pathways

Calcium (Ca 2+ ) plays diverse roles in all living organisms ranging from bacteria to humans. It is a structural element for bones, an essential mediator of excitation-contraction coupling, and a universal second messenger in the regulation of ion channel, enzyme and gene expression activities. In mitochondria, Ca 2+ is crucial for the control of energy production and cellular responses to metabolic stress. Ca 2+ uptake by the mitochondria occurs by the uniporter mechanism. The Mitochondrial Ca2+ Uniporter (MCU) protein has recently been identified as a core component responsible for mitochondrial Ca 2+ uptake. MCU knockout (MCU KO) studies have identified a number of important roles played by this high capacity uptake pathway. Interestingly, this work has also shown that MCU-mediated Ca 2+ uptake is not essential for vital cell functions such as muscle contraction, energy metabolism and neurotransmission. Although mitochondrial Ca 2+ uptake was markedly reduced, MCU KO mitochondria still contained low but detectable levels of Ca 2+ . In view of the fundamental importance of Ca 2+ for basic cell signalling, this finding suggests the existence of other currently unrecognized pathways for Ca 2+ entry. We review the experimental evidence for the existence of alternative Ca 2+ influx mechanisms and propose how these mechanisms may play an integral role in mitochondrial Ca 2+ signalling.