The mitochondrial Ca²⁺ uniporter: Regulation by auxiliary subunits and signal transduction pathways

Mitochondrial Ca²⁺ homeostasis, the Ca²⁺ influx-efflux balance, is responsible for the control of numerous cellular functions, including energy metabolism, generation of reactive oxygen species, spatiotemporal dynamics of Ca²⁺ signaling, and cell growth and death. Recent discovery of the molecular identity of the mitochondrial Ca²⁺ uniporter (MCU) provides new possibilities for application of genetic approaches to study the mitochondrial Ca²⁺ influx mechanism in various cell types and tissues. In addition, the subsequent discovery of various auxiliary subunits associated with MCU suggests that mitochondrial Ca²⁺ uptake is not solely regulated by a single protein (MCU), but likely by a macromolecular protein complex, referred to as the MCU-protein complex (mtCUC). Moreover, recent reports have shown the potential role of MCU posttranslational modifications in the regulation of mitochondrial Ca²⁺ uptake through mtCUC. These observations indicate that mtCUCs form a local signaling complex at the inner mitochondrial membrane that could significantly regulate mitochondrial Ca²⁺ handling, as well as numerous mitochondrial and cellular functions. In this review we discuss the current literature on mitochondrial Ca²⁺ uptake mechanisms, with a particular focus on the structure and function of mtCUC, as well as its regulation by signal transduction pathways, highlighting current controversies and discrepancies.