Mitochondrial Modulation Therapy After Brain Trauma

Abstract Traumatic brain injury (TBI) is a leading cause of death and disability, affecting as many as 1.7 million Americans annually. TBI is a complex and heterogeneous injury that can cause permanent neurological complications and death. The pathophysiology of the progressive secondary injury has been well-studied, revealing a highly complex program of overlapping and sequential processes that leads to ongoing cell death. Despite the heterogeneity in TBI, mitochondria have been identified as a common effector in the cascade to neuronal injury. Following acute neurological injury, post-translational modifications of the electron transport can cause sustained and pathological hyper-activity that generates reactive oxygen species (ROS). Under physiological conditions, mitochondria are strictly maintained through dynamic restructuring and turnover, however dysfunction of these systems is implicated in neurological injury. We have discovered wavelengths of near infrared light (NIR) that partially inhibit cytochrome c oxidase (COX), the rate liming enzyme in the electron transport chain. We have demonstrated this inhibitory effect provides robust neuroprotection in acute neurological injury by preventing mitochondrial hyperactivation and mitigating ROS generation. Our objective in this study will build on our extensive preliminary data by capitalizing expertise from our interdisciplinary research team to: (1) Explore the molecular mechanisms of neurotrauma and therapeutic NIR on mitochondrial dynamics and turnover. (2) Parse the cell-specific mechanisms of NIR therapy following TBI within the constituents of the neurovascular unit. (3) Expand the understanding of therapeutic NIR through alternative treatment application strategies following TBI.