The cell-specific neurodegenerative potential of mitochondria post-traumatic brain injury - Project Summary/Abstract This project responds to PAR-24-022 for the Trailblazer Award for new and early-stage investigators. It will test the hypothesis that injury-induced cell-specific dysregulation in mitochondria bioenergetic and metabolic functions transforms them into neurodegenerative factories that control the onset of acute neuroinflammation, neuronal damage, and the AD-like pathology spread in the long term. Traumatic Brain Injury (TBI) launches a complex cascade of poorly understood neurochemical and neurometabolic abnormalities that lead to long-lasting disabilities and morbidity 1-4. These secondary injury effects are potentially preventable and manifest in energy failure, metabolic dysregulation, chronic glial neuroinflammation, and death of the surrounding tissue 5-7, and recently, researchers implicated TBI as a risk factor for several neurodegenerative disorders, such as Alzheimer’s (AD) 5-8, Parkinson’s disorders (PD) 9,10, or Chronic Traumatic Encephalopathy (CTE) 9 later in life. The devastating long-term consequences of brain injuries urge the scientific community to understand complex intercellular, organellar, and molecular interactions and their contribution to injury progression if we want to succeed in the effective development of diagnostic biomarkers and treatments for TBI patients. Based on the extensive analysis of existing human data and some preliminary experiments from our group, where we observed alterations in the metabolism based on the transcriptomic analysis, secreted metabolites, and miRNA 22-24,35, we postulated that disruption in mitochondrial function is one potential regulator of injury-induced AD-like phenotype progression 8, 9,10. Thus, this project aims to study the cell-specific mitochondria dysfunction hypothesis using a novel approach to studying brain injury and injury-induced AD-like neurodegeneration progression by going from human-based data collection to hypothesis testing in a human in vitro model with genetically inserted fluorescent tags to mitochondria. We will combine neurobiology with neurometabolism to determine in Aim 1) injury-induced intracellular and extracellular mitochondria alterations and validate in Aim 2) the molecular mechanism associated with injury-induced cell-specific mitochondria reuptake. We anticipate building a comprehensive understanding of spatial-temporal changes in mitochondria bioenergetic and metabolic functions after injury and the molecular mechanisms involved in injury-induced AD-like neurodegeneration progression associated with intercellular transfer of dysfunctional mitochondria. This proposal encompasses a novel combination of molecular engineering, genetic, and molecular approaches to provide a comprehensive mechanistic understanding of the response to brain-like tissue injury over a prolonged period with high spatiotemporal resolution. This would help develop criteria for risk assessment and allow for more accurate sensing of neuropathologic damage in TBI patients.
