Flirting in Little Space: The ER/Mitochondria Ca 2+ Liaison

Abstract

Mitochondria have long been known to accumulate Ca 2+ ; the apparent inconsistency between the low affinity of mitochondrial Ca 2+ uptake mechanisms, the low concentration of global Ca 2+ signals observed in cytoplasm, and the efficiency in intact cells of mitochondrial Ca 2+ uptake led to the formulation of the "hotspot hypothesis." This hypothesis proposes that mitochondria preferentially accumulate Ca 2+ at microdomains of elevated Ca 2+ concentration ([Ca 2+ ]) that exist near endoplasmic reticulum (ER) Ca 2+ release sites and other Ca 2+ channels. Physiological Ca 2+ signals may affect mitochondrial function--both by stimulating key metabolic enzymes and, under some conditions, by promoting apoptosis. Mitochondria in turn may affect both Ca 2+ release from the ER and capacitative Ca 2+ entry across the plasma membrane, thereby shaping the size and duration of the intracellular Ca 2+ signal. Interactions between mitochondria and the ER are critically dependent on the spatial localization of mitochondria within the cell. The molecular mechanisms that define the organization of mitochondria with regard to the ER and other Ca 2+ sources, and the extent to which mitochondrial function varies among different cell types, are open questions whose answers remain to be determined.