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bioRxiv · 10.1101/2025.03.19.644244

The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.

Kansakar, S. B.·Sterben, S. P.·Anamala, C. C.·Thielen, M. D.·Liaudanskaya, V.
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Abstract

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 injury-induced neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a novel 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 A{beta}42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes impaired metabolic support and microglia sustained 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.

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Kansakar, S. B., Sterben, S. P., Anamala, C. C., Thielen, M. D., Liaudanskaya, V.. 2025-03-20. The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.. https://doi.org/10.1101/2025.03.19.644244

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