Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury

Preethy S. Sridharan, Yeojung Koh, Emiko Miller, Di Hu, Suwarna Chakraborty, Sunil Jamuna Tripathi, Teresa R. Kee, Kalyani Chaubey, Edwin Vázquez-Rosa, Sarah Barker, Hui Liu, Rose A. León-Alvarado, Kathryn Franke, Coral J. Cintrón-Pérez, Matasha Dhar, Min Kyoo Shin, Margaret E. Flanagan, Rudolph J. Castellani, Tamar Gefen, Marina BykovaLijun Dou, Feixiong Cheng, Brigid M. Wilson, Hisashi Fujioka, David E. Kang, Jung A.A. Woo, Bindu D. Paul, Xin Qi, Andrew A. Pieper

Research output: Contribution to journalArticlepeer-review

Abstract

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI. Pharmacologically preventing Fis1 from binding its mitochondrial partner, dynamin-related protein 1 (Drp1), for 2 weeks after TBI normalizes the balance of mitochondrial fission/fusion and prevents chronically impaired mitochondrial bioenergetics, oxidative damage, microglial activation and lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, and cognitive impairment. Delaying treatment until 8 months after TBI offers no protection. Thus, time-sensitive inhibition of acutely elevated mitochondrial fission may represent a strategy to protect human TBI patients from chronic neurodegeneration.

Original languageEnglish (US)
Article number101715
JournalCell Reports Medicine
Volume5
Issue number9
DOIs
StatePublished - Sep 17 2024

Keywords

  • Drp1
  • Fis1
  • blood-brain barrier
  • mitochondria
  • mitochondrial fission
  • mitochondrial fusion
  • neurodegeneration
  • neuroprotection
  • oxidative stress
  • traumatic brain injury

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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