CaMKII does it again: even the mitochondria cannot escape its influence.

A lthough the recent identification of the mitochondrial Ca 2+ uniporter (MCU) has resolved a long-standing mystery as to how Ca 2+ freely enters the mitochondria, it has also evoked additional questions such as its mode of regulation and the identity of other associated factors. In an article recently published in Nature, Joiner et al 1 provide data demonstrating that in the heart, matrix-localized Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) can upregulate MCU activity in a manner requiring phos-phorylation of the channel N terminus. They showed that inhibition of CaMKII-dependent MCU activity protected the heart from ischemic injury by presumably reducing Ca 2+ influx and desensitizing the mitochondrial perme-ability transition pore (MPTP) to opening. Although these results demonstrate convincingly that CaMKII plays an important role in MCU regulation and subsequent response to cardiac injury, several questions remain unanswered. The ability of mitochondria to take up and sequester Ca 2+ plays an important role in the buffering of cytosolic Ca 2+ , regulation of ATP production via the citric acid cycle, and regulation of apoptotic and necrotic cell death pathways.