The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
Traumatic brain injury (TBI) is a major risk factor for neurodegenerative diseases, including Alzheimers disease (AD), yet the mechanistic link remains unclear. Here, we integrated human patient-derived transcriptomics with a 3D in vitro brain injury model to dissect cell-specific mitochondrial dysfunction as a driver of neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a one-of-a-kind cell-specific mitochondria tracking system, we demonstrate prolonged neuronal mitochondrial fragmentation, bioenergetic failure, and metabolic instability, coinciding with the emergence of AD markers, including pTau, APP, and Abeta 42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes failing to maintain metabolic support and microglia sustaining chronic inflammation. These findings establish neuronal mitochondrial failure as an early trigger of injury-induced neurodegeneration, reinforcing mitochondrial dysfunction as a therapeutic target for preventing TBI-driven AD pathology.