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

Autor:	Sridharan PS; 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., Koh Y; 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., Miller E; 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., Hu D; Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Chakraborty S; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Tripathi SJ; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Kee TR; 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., Chaubey K; 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., Vázquez-Rosa E; 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., Barker S; 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., Liu H; 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., León-Alvarado RA; 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., Franke K; 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., Cintrón-Pérez CJ; 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., Dhar M; 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., Shin MK; 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., Flanagan ME; 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., Castellani RJ; 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., Gefen T; 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., Bykova M; Department of Regulatory Biology, Cleveland State University, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Dou L; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Cheng F; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Wilson BM; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Louis Stokes VA Medical Center, Cleveland, OH, USA., Fujioka H; Cryo-Electron Microscopy Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Kang DE; 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., Woo JA; 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., Paul BD; 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., Qi X; Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address: xxq38@case.edu., Pieper AA; 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. Electronic address: andrew.pieper@case.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Sep 17; Vol. 5 (9), pp. 101715. Date of Electronic Publication: 2024 Sep 05.
DOI:	10.1016/j.xcrm.2024.101715
Abstrakt:	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. Competing Interests: Declaration of interests X.Q. is an inventor of P110 and holds patents related to P110. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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