Mitochondrial dysfunction and PANoptosis-related signaling in acute central nervous system injuries: mechanistic convergence and therapeutic opportunities.

Acute central nervous system (CNS) injuries comprise a heterogeneous group of disorders caused by vascular or traumatic factors, including ischemic stroke, intracerebral hemorrhage (ICH), traumatic brain injury (TBI), and spinal cord injury (SCI). These injuries initiate secondary cascades that combine metabolic failure, oxidative stress, neuroinflammation, and regulated cell death. Mitochondrial dysfunction is positioned near the center of these processes because impaired bioenergetics, excessive mitochondrial reactive oxygen species (mtROS), abnormal fission and fusion, defective mitophagy, and mitochondrial DNA (mtDNA) release can simultaneously disturb cellular homeostasis and activate inflammatory signaling. PANoptosis is an inflammatory form of regulated cell death that integrates pyroptotic, apoptotic, and necroptotic machinery through PANoptosome complexes. Emerging evidence suggests that mitochondrial stress can create conditions that favor PANoptotic convergence by increasing mtROS and damage-associated molecular patterns (DAMPs), activating DNA-sensing and inflammasome pathways, and sustaining receptor-interacting protein kinase and caspase signaling. This review examines the potential mechanistic links between mitochondrial dysfunction and PANoptosis-related signaling across ischemic stroke, ICH, SCI, and TBI. We summarize changes in mitochondrial bioenergetics, oxidative stress, dynamics, mitophagy, mitochondria-derived vesicles (MDVs), and mitochondrial transfer, and evaluate how these changes intersect with PANoptosis-related signaling. Importantly, we distinguish direct evidence of PANoptosis from studies that only demonstrate coordinated changes in individual death pathways. We also assess therapeutic strategies that target mitochondrial oxidative stress, dynamics, mitophagy, biogenesis, mitochondrial DAMP signaling, and mitochondrial transplantation and transfer. Current findings support mitochondria as a promising upstream intervention point, but complete causal evidence linking mitochondrial damage to defined PANoptosome assembly remains limited in acute CNS injury. Clarifying cell-specific and time-dependent mechanisms will be essential for translating this framework into effective neuroprotective strategies.