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.

Characterization of PANoptosis-related genes and the immune landscape in moyamoya disease

“…Recent trends in PANoptosis have led to a proliferation of studies of altered genes in tumors 10 – 12 . However, within vascular disease, comparably little attention has been given to possible roles for PANoptosis 13 , 14 . Previous studies have suggested that apoptosis and smooth muscle cell (SMC) proliferation may play an important role in arterial remodeling in MMD 15 .…”

Progress of medicinal plants and their active metabolites in ischemia-reperfusion injury of stroke: a novel therapeutic strategy based on regulation of crosstalk between mitophagy and ferroptosis

“…Therefore, it is an urgent global need to explore the comprehensive pathogenic mechanisms and effective diagnostic and therapeutic methods for ischemic stroke. Increasing evidence suggests that ischemia-reperfusion injury is an important link in the pathogenesis of ischemic stroke, and in this process, the regulation of cellular physiological processes such as mitophagy and ferroptosis becomes particularly crucial ( Liu et al, 2013 ; Zhang et al, 2022a ; She et al, 2023 ). Ischemia-reperfusion injury in cerebral strokeresults from cellular damage due to insufficient cerebral blood flow, exacerbated by oxidative stress and inflammatory reactions during reperfusion.…”

Novel Therapeutic Strategy Targeting Hspa8 for Ischemic Brain Injury

“…This in ammatory response exacerbates brain tissue damage and potentially hinders neural functional recovery. Therefore, a thorough understanding of the pathophysiological mechanisms of ischemic brain injury, particularly the role of immune-in ammatory responses, is crucial for developing novel therapeutic strategies (10,11,12).…”