Mitochondrial Ca uptake pathways.

Calcium (Ca) 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 is crucial for the control of energy production and cellular responses to metabolic stress. Ca 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 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 uptake is not essential for vital cell functions such as muscle contraction, energy metabolism and neurotransmission. Although mitochondrial Ca uptake was markedly reduced, MCU KO mitochondria still contained low but detectable levels of Ca. In view of the fundamental importance of Ca for basic cell signalling, this finding suggests the existence of other currently unrecognized pathways for Ca entry. We review the experimental evidence for the existence of alternative Ca influx mechanisms and propose how these mechanisms may play an integral role in mitochondrial Ca signalling.