Mitochondrial homeostasis imbalance-triggered PANoptosis in traumatic brain and spinal cord injury: from mechanism to therapeutic strategies.

Traumatic injury to the central nervous system (CNS), also known as traumatic brain injury (TBI) and spinal cord injury (SCI), is characterized by high disability and mortality worldwide. PANoptosis is a newly identified cell death mode that synergistically initiates pyroptosis, apoptosis and necroptosis via activation of PANoptosome. It is closely associated with oxidative stress, neuroinflammation, and secondary injury following TBI and SCI, yet the key pathogenic factors and mechanisms underlying PANoptosis remain incompletely elucidated. Mitochondria, as a central organelle for energy synthesis and oxidative stress, its health and homeostasis are the cornerstone of cell survival and biological function. Emerging evidence suggests that the loss of mitochondrial homeostasis plays a fundamental role in the activation and execution of PANoptosis across various cell types. Here, we review the detailed manifestations of mitochondrial homeostasis imbalance in TBI and SCI, such as impaired biogenesis, abnormal dynamics, mitophagy dysfunction, and mitochondria-derived vesicles. Meanwhile, we systematically analyze the characteristics and pathological effects of PANoptosis cascade following TBI and SCI, with a focus on the regulatory patterns, mechanisms, and potential targets of injured mitochondria driving PANoptosis. In addition, we discuss the advancements and future perspectives of mitochondria-based strategies for modulating PANoptosis in TBI and SCI. Taken together, despite considerable challenges in governing post-traumatic mitochondria homeostasis, its multiple targeting of the upstream PANoptosome and downstream cell death signaling offers a promising approach to improve the outcome of CNS trauma.