FIGURE 2.

Dynamic regulation of mitochondrial Ca²⁺ handling and respiration by MICU1 and OPA1 in cristae. (A) Glutamate (blue) activates the NMDA receptor (NMDAR) resulting in Ca²⁺ influx. Ca²⁺ then crosses the OMM via VDAC. Under basal conditions, MCU and EMRE subunits confer MCU_cx activity that transports Ca²⁺ into the matrix. Ca²⁺ allosterically activates dehydrogenases in the tricarboxylic acid cycle (TCA) that generate reducing equivalents which drive proton (H⁺) pumping by Complexes I, III, and IV (large green arrow). ATP synthase harvests this proton gradient to manufacture ATP. MICOS, OPA1, and MICU1 hexamers located at the cristae junction (CJ) oppose the movements of Ca²⁺ into and H⁺ out (small green line) of the cristae lumen. (B) Increased glutamate release enhances NMDAR activation resulting in elevated Ca²⁺ entry into the cytosol. VDAC then transports greater amounts of Ca²⁺ across the OMM. The resultant elevation of Ca²⁺ in the intramembrane space triggers the dissociation of MICU1 subunits that recruit MCU and EMRE subunits from the cristae. (C) Pathological depletion of MICU1 opens the CJ allowing Ca²⁺ to enter (red arrow) and cytochrome c and H⁺ to escape (large green arrow) the cristae lumen. This uncouples the electron transport chain resulting in reduced ATP synthesis, increased ROS production and cytochrome c-induced cell death. Adapted from Gottschalk et al., 2022. (See section “2.2. MICU1 regulates cristae junction dynamics and spatially anchors the MCUcx” for abbreviations and mechanistic details).