Mitochondrial dysfunctions induce PANoptosis and ferroptosis in cerebral ischemia/reperfusion injury: from pathology to therapeutic potential

Abstract

Ischemic stroke (IS) accounts for more than 80% of the total stroke, which represents the leading cause of mortality and disability worldwide. Cerebral ischemia/reperfusion injury (CI/RI) is a cascade of pathophysiological events following the restoration of blood flow and reoxygenation, which not only directly damages brain tissue, but also enhances a series of pathological signaling cascades, contributing to inflammation, further aggravate the damage of brain tissue. Paradoxically, there are still no effective methods to prevent CI/RI, since the detailed underlying mechanisms remain vague. Mitochondrial dysfunctions, which are characterized by mitochondrial oxidative stress, Ca²⁺ overload, iron dyshomeostasis, mitochondrial DNA (mtDNA) defects and mitochondrial quality control (MQC) disruption, are closely relevant to the pathological process of CI/RI. There is increasing evidence that mitochondrial dysfunctions play vital roles in the regulation of programmed cell deaths (PCDs) such as ferroptosis and PANoptosis, a newly proposed conception of cell deaths characterized by a unique form of innate immune inflammatory cell death that regulated by multifaceted PANoptosome complexes. In the present review, we highlight the mechanisms underlying mitochondrial dysfunctions and how this key event contributes to inflammatory response as well as cell death modes during CI/RI. Neuroprotective agents targeting mitochondrial dysfunctions may serve as a promising treatment strategy to alleviate serious secondary brain injuries. A comprehensive insight into mitochondrial dysfunctions-mediated PCDs can help provide more effective strategies to guide therapies of CI/RI in IS.

Keywords: PANoptosis; PANoptosome; cerebral ischemia/reperfusion injury (CI/RI); ferroptosis; ischemic stroke; mitochondrial dysfunctions.

FIGURE 1

Overview of mitochondrial dysfunctions during CI/RI. Mitochondria are the most susceptible organelle to CI/RI. ATP consumption, glucose/O₂ deprivation, burst of ROS, Ca²⁺ overload, excitotoxicity, inflammatory response and other consequences of CI/RI could trigger mitochondrial dysfunctions including mitochondrial oxidative stress, Ca²⁺ overload, iron dyshomeostasis, mitochondrial DNA defects, mitochondrial quality control disruption as well as mitochondrial-induced PCDs. These cellular processes ultimately lead to the death of neuron.

FIGURE 2

PANoptosis pathways. Exposure to stimulus during CI/RI can lead to the initiation of the apical sensors, such as ZBP1, which then induces the activation of proteins involved in pyroptosis, apoptosis, and necroptosis to form the ZBP1-PANoptosome and mediate PANoptosis. Three arms of cell death are executed by GSDMD family proteins (pyoptosis), caspase-3/7/8 (apoptosis) and MLKL (necroptosis). TAK1 could block formation of the PANoptosome and induction of PANoptosis.

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.