Mitochondrial oxidative stress to PANoptosis: Current evidence and therapeutic implications for neurological diseases

Abstract

• Mitochondrial dysfunction and oxidative stress are key drivers of neurodegeneration. • PANoptosis exacerbates neuronal dysfunction and cell death in neurological diseases. • Mitochondrial dysfunctions and oxidative stress are key inducers of PANoptosis activation. • Mitochondria-targeted antioxidants hold significant potential for inhibiting PANoptosis. • PANoptosis inhibition demonstrates multiple neuroprotective effects in neurological disease. Mitochondrial oxidative stress is a key driver of neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and spinal cord injury, promoting neuronal dysfunction and degeneration through multiple pathways. PANoptosis, a recently characterized regulated cell death pathway integrating pyroptotic, apoptotic, and necroptotic signaling, exacerbates neuroinflammation and accelerates neuron loss. Emerging evidence reveals the important role of mitochondrial oxidative stress in inducing PANoptosis through complex mechanisms associated with reactive oxygen species overproduction, mitochondrial DNA damage, and impaired mitochondrial dynamics. This review aims to summarize current knowledge on the mechanisms and roles of PANoptosis in neurological diseases, with a focus on its interplay with mitochondrial oxidative stress. This review provides insight into the intricate crosstalk between mitochondrial oxidative stress and the activation of PANoptosis, particularly through caspase activation, necroptotic signaling, and pyroptotic pathways. Furthermore, we highlight emerging therapeutic interventions that target these mechanisms. These strategies have shown promise in attenuating neuroinflammation and neuronal death, offering hope for the development of targeted therapies to address the complex pathophysiology of neurological diseases.

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