FIGURE 3.

The mechanism of mitochondrial dysfunctions induced PANoptosis and ferroptosis during CI/RI. Mitochondria play essential roles in pathological conditions after ischemic stroke and reperfusion. During ischemia, oxygen–glucose deprivation will cause ATP consumption and the bind of death ligands to death receptors on the membrane. Na⁺/K⁺ ATPase pump failure that induces depolarization of neuronal membranes and extreme release of glutamate, burst of ROS, free radical damage, Ca²⁺ homeostasis disorder and EAA toxicity, etc. Iron was released into the brain parenchyma, which accelerates lipid ROS accumulation and ferroptosis via Fenton reaction. The extracellular death ligands bind to death receptors, which triggers the recruitment of FADD or TRADD to induce apoptosis and necroptosis, respectively. These mechanisms cause mitochondrial dysfunctions such as formation of mPTP, burst of mtROS, mitochondrial Ca²⁺ overload and mtDNA damage, which could execute different cell death pathways.