Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury
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.
Authors
- Kathryn Franke (ORCID: https://orcid.org/0000-0002-3038-2826)
- Margaret E. Flanagan (ORCID: https://orcid.org/0009-0008-7078-3545)
- Bindu D. Paul (ORCID: https://orcid.org/0000-0002-1862-6103)
- Rudolph J. Castellani (ORCID: https://orcid.org/0000-0002-5414-3184)
- Jung A. Woo (ORCID: https://orcid.org/0000-0002-9194-1361)
- Sarah Barker
- Feixiong Cheng (ORCID: https://orcid.org/0000-0002-1736-2847)
- Kalyani Chaubey (ORCID: https://orcid.org/0000-0002-6378-6739)
- Tamar Gefen (ORCID: https://orcid.org/0000-0002-2380-3100)
- Teresa R. Kee (ORCID: https://orcid.org/0000-0003-4140-6341)
- Emiko Miller (ORCID: https://orcid.org/0000-0003-3396-591X)
- Preethy S. Sridharan (ORCID: https://orcid.org/0000-0001-7692-6342)
- Yeojung Koh (ORCID: https://orcid.org/0000-0002-4294-7871)
- Sunil Jamuna Tripathi (ORCID: https://orcid.org/0000-0001-9107-2437)
- Hisashi Fujioka (ORCID: https://orcid.org/0000-0001-8511-7141)
- Xin Qi (ORCID: https://orcid.org/0000-0002-9578-3890)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Suwarna Chakraborty (ORCID: https://orcid.org/0000-0001-9456-4322)
- Brigid Wilson (ORCID: https://orcid.org/0000-0003-2966-2940)
- David E. Kang (ORCID: https://orcid.org/0000-0002-7132-821X)
- Di Hu (ORCID: https://orcid.org/0000-0003-4047-7340)
- Matasha Dhar (ORCID: https://orcid.org/0000-0003-1714-0424)
- Coral J. Cintrón-Pérez (ORCID: https://orcid.org/0000-0003-2160-4244)
- Edwin Vázquez‐Rosa (ORCID: https://orcid.org/0009-0005-4508-5217)
- Hui Liu (ORCID: https://orcid.org/0000-0002-7669-9386)
- Lijun Dou
- Min-Kyoo Shin (ORCID: https://orcid.org/0000-0001-6697-3639)
- Rose A León-Alvarado (ORCID: https://orcid.org/0000-0002-4525-4958)
- Marina Bykova
Institutions
- Northwestern University (US)
- Johns Hopkins University (US)
- The University of Texas at San Antonio Health Science Center (US)
- University Hospitals of Cleveland (US)
- Johns Hopkins Medicine (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Louis Stokes Cleveland VA Medical Center (US)
- Cleveland Research (United States) (US)
- University School (US)
- Case Western Reserve University (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101715
- Citations
- 27
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 6.31
Funders
- National Institutes of Health