Mitochondrial Ca²⁺ influx and efflux mechanisms. Schematic diagram of mitochondrial Ca²⁺ channels/transporters for influx and efflux mechanisms. The functional and morphological tight coupling of ER/SR (yellow) and mitochondria is attributed to the specific structure of inter-organelle tether proteins such as mito-fusion protein 2 (gray) (de Brito and Scorrano, 2008; García-Pérez et al., 2011). Ca²⁺-releasing sites of ER/SR, IP₃ receptors (IP₃R), or RyRs (RyR; green) are facing microdomains between mitochondria and ER/SR (shown as a pink region). Ca²⁺ release from ER/SR dramatically changes [Ca²⁺]_c at this microdomain (Csordás et al., 2010; Giacomello et al., 2010). Then, mitochondria sense the high increases of [Ca²⁺]_c at this microdomain, and [Ca²⁺]_c propagates into the mitochondria matrix through a variety of Ca²⁺ channels/transporters (Rizzuto et al., 1992). Mitochondrial Ca²⁺ influx (upper part of this figure) is determined by the MCU (blue) (Baughman et al., 2011; De Stefani et al., 2011), RaM (black) (Sparagna et al., 1995; Buntinas et al., 2001; Bazil and Dash, 2011), HCX (Letm1; orange) (Jiang et al., 2009), mRyR1 (red) (Beutner et al., 2001, 2005), hydroxyl coenzyme Q10 (CoQs) (Bogeski et al., 2011), mCa1 and mCa2 (Michels et al., 2009), and UCP 2 and UPC 3 (Trenker et al., 2007) located at the IMM. MICU1 can bind to Ca²⁺ by its EF hand, but this protein does not make the channel pore because of its single-transmembrane structure (Perocchi et al., 2010). The mPTP (black) (Giacomello et al., 2007), NCX (purple) (Palty et al., 2010), and HCX (orange) (Jiang et al., 2009) contribute to Ca²⁺ efflux (lower part of this figure) in mammalian cells. Drosophila mitochondria possess another selective Ca²⁺ release channel (DroCRC; black) with unique featured characteristics intermediate between the permeability transition pore of yeast and mammals (von Stockum et al., 2011). Letm1 also works as a Ca²⁺ efflux pathway when [Ca²⁺]_c becomes high (Jiang et al., 2009) (see also Figs. 2 and 3 E). Voltage-dependent anion-selective channels (VDAC; dark green) provide a pathway for Ca²⁺ and metabolite transport across the outer mitochondrial membrane (OMM). The channels/transporters for which molecular identities are still unknown are shown as black. Red arrows show Ca²⁺ movements, and blue arrows show other ion movements.