FIGURE 5.

Ca²⁺, Mn²⁺, Zn²⁺, and Fe²⁺ uptake by the MCU_cx triggers mitochondrial collapse and multiple cell death pathways. Boxes 1–3, Ischemia causes excessive mitochondrial Ca²⁺, Mn²⁺, and Zn²⁺ uptake by the MCU_cx resulting in injurious ROS overproduction and the release of multiple pro-death factors (SMAC, AIF, CytoC, and DAMPs). Boxes 4–6, Bleeding triggers excessive mitochondrial Fe²⁺ uptake by the MCU_cx that results in ROS overproduction and the release of pro-death factors (SMAC, AIF, CytoC, and DAMPs). Boxes 7, 8, Mitochondrial collapse impairs Ca²⁺ buffering and ATP synthesis that exacerbates the injurious effects of ROS overproduction and pro-death factor release. (See section “6.3. MCUcx inhibition blocks multiple cell death pathways implicated in ischemic and hemorrhagic damage of the NVU” for abbreviations and mechanistic details).