Modulation of the matrix redox signaling by mitochondrial Ca2+

Figure 1 Ca²⁺ transport proteins of mitochondria. In mammalian mitochondria, the uptake of Ca²⁺ is mediated by the Ca²⁺-selective channel MCU, which is part of a high molecular weight protein complex called Uniplex. At least 4 additional proteins (MCUb, MICU1, MICU2 and EMRE) regulate MCU activity. Ca²⁺ is then extruded by a sodium/calcium exchange (NCX) or proton/calcium exchange (HCX). If the protein NCLX has been confirmed to be the mitochondrial NCX, which is down-regulated by the protein SLP-2, the molecular nature of the mitochondrial HCX is still debated. Dimers of mitochondrial ATP synthase have been proposed to form the PTP, a mitochondrial channel regulated by CypD, that facilitates PTP opening by desensitizing PTP to Ca²⁺. Besides being activated by Ca²⁺, PTP has also been proposed to act as a reversible fast Ca²⁺ release channel. Other non-MCU mitochondrial proteins with an indirect or debated effect on Ca²⁺ transport are represented in the blue square (MCUR; SLC25A23; ryanodine receptor, RyR; UCP2; UCP3; LETM1). OMM: Outer mitochondrial membrane; IMS: Inter-membrane space; IMM: Inner mitochondrial membrane; VDAC: Mitochondrial porin; PTP: Permeability transition pore; CypD: Cyclophilin D; MCU: Mitochondrial Ca²⁺ uniporter; MCUR1: Mitochondrial calcium uniporter regulator 1; MICU1: Mitochondrial Ca²⁺ uptake protein 1; MICU2: Mitochondrial Ca²⁺ uptake protein 2; EMRE: Essential MCU regulator.