Cell Reports Medicine (Sep 2024)
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 Bykova,
- Lijun Dou,
- Feixiong Cheng,
- Brigid M. Wilson,
- Hisashi Fujioka,
- David E. Kang,
- Jung-A.A. Woo,
- Bindu D. Paul,
- Xin Qi,
- Andrew A. Pieper
Affiliations
- Preethy S. Sridharan
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Yeojung Koh
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Emiko Miller
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Di Hu
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Suwarna Chakraborty
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sunil Jamuna Tripathi
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Teresa R. Kee
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Molecular Medicine, USF Health College of Medicine, Tampa, FL, USA
- Kalyani Chaubey
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Edwin Vázquez-Rosa
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Sarah Barker
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Hui Liu
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Rose A. León-Alvarado
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Earlham College Neuroscience Program, Richmond, IN, USA
- Kathryn Franke
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Coral J. Cintrón-Pérez
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Matasha Dhar
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Min-Kyoo Shin
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08226, Republic of Korea
- Margaret E. Flanagan
- University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Glenn Bigg’s Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Rudolph J. Castellani
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Tamar Gefen
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Marina Bykova
- Department of Regulatory Biology, Cleveland State University, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Lijun Dou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Brigid M. Wilson
- Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Louis Stokes VA Medical Center, Cleveland, OH, USA
- Hisashi Fujioka
- Cryo-Electron Microscopy Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- David E. Kang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Molecular Medicine, USF Health College of Medicine, Tampa, FL, USA; Louis Stokes VA Medical Center, Cleveland, OH, USA
- Jung-A.A. Woo
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Molecular Medicine, USF Health College of Medicine, Tampa, FL, USA
- Bindu D. Paul
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Lieber Institute for Brain Development, Baltimore, MD, USA
- Xin Qi
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Corresponding author
- Andrew A. Pieper
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Corresponding author
- Journal volume & issue
-
Vol. 5,
no. 9
p. 101715
Abstract
Summary: 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.
