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

Abstract

Mitochondrial Ca(2+) homeostasis, the Ca(2+) influx-efflux balance, is responsible for the control of numerous cellular functions, including energy metabolism, generation of reactive oxygen species, spatiotemporal dynamics of Ca(2+) signaling, and cell growth and death. Recent discovery of the molecular identity of the mitochondrial Ca(2+) uniporter (MCU) provides new possibilities for application of genetic approaches to study the mitochondrial Ca(2+) influx mechanism in various cell types and tissues. In addition, the subsequent discovery of various auxiliary subunits associated with MCU suggests that mitochondrial Ca(2+) 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 Ca(2+) uptake through mtCUC. These observations indicate that mtCUCs form a local signaling complex at the inner mitochondrial membrane that could significantly regulate mitochondrial Ca(2+) handling, as well as numerous mitochondrial and cellular functions. In this review we discuss the current literature on mitochondrial Ca(2+) 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.

Mitochondrial calcium uniporter in Drosophila transfers calcium between the endoplasmic reticulum and mitochondria in oxidative stress-induced cell death

“…In mammalian cells, suppression of EMRE abrogates MCU-mediated Ca 2ϩ currents demonstrated by mitoplast patch clamp experiment (12,14). However, functional consequences of EMRE overexpression have not been studied yet (44). In our study, EMRE showed a strong genetic interaction with MCU in Drosophila.…”

Crosstalk between calcium and reactive oxygen species signaling in cancer

“…MCU comprises the pore-forming unit of a complex of proteins that includes regulatory proteins involved in gating of MCU (for review see [325]). The role of MCU-regulated mitochondrial Ca 2+ uptake on maintaining mitochondrial bioenergetics is dependent on the relative metabolic activity of specific tissues, as demonstrated in MCU knockout animals, where loss of MCU has little effect on Oxidative Phosphorylation of mouse embryonic fibroblasts.…”

Mitochondrial clearance of Ca2+controls insulin secretion

“…The molecular characterization of the uniporter (Baughman et al, 2011, De Stefani, Raffaello et al, 2011, Perocchi et al, 2010, Plovanich et al, 2013, as well as a number of accessory proteins, i.e., MICU1, 2, 3 and EMRE (Perocchi et al, 2010, Plovanich et al, 2013, Sancak et al, 2013 opened the possibility of genetic manipulation of the components of the uniporter (Jhun et al, 2016). It was shown that silencing of Mcu abrogates the rise in [Ca 2+ ] mito and the cytosolic ATP/ADP ratio in response to glucose in mouse -cells (Tarasov, Semplici et al, 2012).…”

“…Mitochondrial Ca 2+ uptake in most cells occurs via a macromolecular protein complex, known as the calcium uniporter holocomplex (Jhun, Mishra et al, 2016, Sancak, Markhard et al, 2013. MCU forms the central pore-forming subunit of the complex, while MCU regulatory subunit b (MCUb), essential MCU regulator (EMRE), mitochondrial uptake 1 and 2 (MICU1 and MICU2) form the accessory components (Kamer & Mootha, 2015).…”