Mitochondrial Dysfunction Drives Traumatic Brain Injury Pathology, Offering Theranostic Avenues

Traumatic brain injury (TBI) affects up to 69 million people annually, posing a significant global health burden. Its pathophysiology involves both immediate primary injury and evolving secondary injury mechanisms like excitotoxicity, oxidative stress, calcium dysregulation, and neuroinflammation. Current treatments often fall short in addressing these complex, delayed processes. Mitochondria, central to cellular energy and signaling, are intimately involved in these secondary injury pathways, making their dysfunction a critical target for understanding and intervening in TBI progression.

This comprehensive review synthesizes current literature on the role of mitochondrial dysfunction in the pathophysiology of Traumatic Brain Injury (TBI). The authors systematically analyzed existing research to delineate how mitochondrial impairment contributes to both the acute and long-term sequelae of TBI, exploring its implications for developing novel diagnostic (theranostic) and therapeutic strategies. The review integrates findings across molecular, cellular, and macroscopic levels of injury.

The review establishes that mitochondrial dysfunction is a pivotal event in the secondary injury cascade following TBI. It contributes to neuronal death via apoptosis, necrosis, and ferroptosis, and exacerbates neuroinflammation through glial activation. Impaired mitochondrial function leads to bioenergetic failure, increased production of reactive oxygen species, and calcium dysregulation, all of which propagate cellular damage.

Mitochondrial involvement extends to synaptic dysfunction, dendritic spine loss, and impaired neurovascular coupling, ultimately contributing to diffuse axonal injury and blood-brain barrier disruption. The synthesis highlights that these mitochondrial perturbations are not merely consequences but active drivers of TBI pathology, suggesting a critical window for intervention.