Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Gerben van Hameren, Jamil Muradov, Anna Minarik, Refat Aboghazleh, Sophie Orr, Shayna Cort, Keiran Andrews, Caitlin McKenna, Nga Thy Pham, Mark A. MacLean, Alon Friedman

Research output: Contribution to journalArticlepeer-review


Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.

Original languageAmerican English
Article number106269
JournalNeurobiology of Disease
StatePublished - 1 Oct 2023


  • Cortical spreading depolarization
  • Electrocorticography
  • In vivo microscopy
  • Mitochondria
  • Neurovascular coupling
  • Reactive oxygen species
  • Seizures
  • Traumatic brain injury
  • electron microscopy

All Science Journal Classification (ASJC) codes

  • Neurology


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