ArticleCell reports. Medicine2024
Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.
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31citing papers in PubMed
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31 citing papers in PubMed.
- PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Mitochondrial homeostasis imbalance-triggered PANoptosis in traumatic brain and spinal cord injury: from mechanism to therapeutic strategies.Redox biology · 2026Review
- Acupuncture regulates mitochondrial homeostasis in traumatic brain injury: current evidence, mechanistic hypotheses, and translational challenges.Chinese medicine · 2026Review
- Electroacupuncture Prevents TBI-Induced Synaptic Loss by Inhibiting CaMKII/Drp1-Dependent Mitochondrial Fission.Biomolecules · 2026Article
- Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.CNS neuroscience & therapeutics · 2026Review
- Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.Research square · 2026Article
- Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Brain Serotonin Deficiency Impairs Ovarian Reserve Function via the Hypothalamic-Pituitary-Ovarian Axis.Neuroscience bulletin · 2026Article
- Mitochondrial Dysfunction in Traumatic Brain Injury and Its Theranostic Implications.Biomolecules · 2026Review
- Restoring mitochondrial health after blast-induced traumatic brain injury: modifiable factors and therapeutic opportunities.npj metabolic health and disease · 2026Review
- Elovanoid neuroprotection targets cell transcriptomics and proteomics to sustain synaptic integrity after brain injury.Communications biology · 2026Article
- Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.Experimental neurology · 2026Article
- Endoplasmic Reticulum-Mitochondrial Crosstalk in Calcium Regulation: Mechanistic Insights and Therapeutic Implications in Traumatic Brain Injury.Molecular neurobiology · 2026Review
- Dynamin-Related Protein 1-Dependent Disruption of Mitochondrial Homeostasis Drives Blue Light-Induced Epithelial-Mesenchymal Transition in Retinal Aging.Aging cell · 2026Article
- Mild traumatic brain injury promotes chronic cerebrovascular inflammation and glymphatic suppression.Molecular neurodegeneration advances · 2026Article
- Current perspectives on circadian regulation of mitochondrial dynamics in mood disorders and perioperative stress.Frontiers in pharmacology · 2026Review
- Network-based prediction and real-world patient data observation identify doxycycline as a repurposable drug in Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Molecular mechanisms of exercise-induced neuroprotection against Parkinson's disease.Sports medicine and health science · 2026Review
- Cystathionine γ-lyase is a major regulator of cognitive function through neurotrophin signaling and neurogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.Molecular neurodegeneration · 2025Article
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Authors and funding
29 authors.
Preethy S SridharanDepartment 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 KohDepartment 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 MillerDepartment 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 HuDepartment of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Suwarna ChakrabortyDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sunil Jamuna TripathiDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Teresa R KeeDepartment 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 ChaubeyDepartment 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-RosaDepartment 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 BarkerDepartment 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 LiuDepartment 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-AlvaradoDepartment 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 FrankeDepartment 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-PérezDepartment 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 DharDepartment 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 ShinDepartment 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 FlanaganUniversity 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 CastellaniMesulam 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 GefenMesulam 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 BykovaDepartment of Regulatory Biology, Cleveland State University, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Lijun DouGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Feixiong ChengGenomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Brigid M WilsonGeriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Louis Stokes VA Medical Center, Cleveland, OH, USA.
Hisashi FujiokaCryo-Electron Microscopy Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
David E KangDepartment 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 WooDepartment 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 PaulDepartment 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 QiDepartment of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address: xxq38@case.edu.
Andrew A PieperDepartment 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.
Funding
TUMOR METABOLISM PROGRAMP30CA043703 · NCI · CASE WESTERN RESERVE UNIVERSITY · PI Amar Desai · 1987 to 2026
$142.3MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007250 · NIGMS · CASE WESTERN RESERVE UNIVERSITY · PI HUANG, ALEX YEE-CHEN · 1985 to 2023
$33.4MResearch Education Core FP30AG072977 · NIA · NORTHWESTERN UNIVERSITY AT CHICAGO · PI CHANGIZ GEULA · 2021 to 2026
$26.3MThorase Regulation of the Actions of CocaineP50DA044123 · NIDA · JOHNS HOPKINS UNIVERSITY · PI BARABAN, JAY M · 2018 to 2022
$9.0MChemical, Structural and Cell-Signaling Interrogation of 15-Prostanglandin Dehydrogenase in Tissue Repair and RegenerationRM1GM142002 · NIGMS · UT SOUTHWESTERN MEDICAL CENTER · PI MARKOWITZ, SANFORD D., PIEPER, ANDREW A · 2021 to 2025
$6.9MMedical Scientist Training Program at Case Western Reserve UniversityT32GM152319 · NIGMS · CASE WESTERN RESERVE UNIVERSITY · PI Heather Broihier, Alex Yee-Chen Huang · 2024 to 2026
$5.1MEndophenotype Network-based Approaches to Prediction and Population-based Validation of In Silico Drug Repurposing for Alzheimer's DiseaseR01AG066707 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Feixiong Cheng · 2020 to 2026
$4.9MAlzheimer's MultiOme Data Repurposing: Artificial Intelligence, Network Medicine, and Therapeutics DiscoveryU01AG073323 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI BEKRIS, LYNN, CHENG, FEIXIONG · 2021 to 2025
$4.0MNeuroprotective actions of cystathionine g-lyase through gasotransmitter hydrogen sulfide signalingR01AG071512 · NIA · JOHNS HOPKINS UNIVERSITY · PI Bindu Paul · 2022 to 2026
$3.4MMechanism of white matter pathology in Alzheimer's diseaseR01AG076051 · NIA · CASE WESTERN RESERVE UNIVERSITY · PI XIN QI · 2022 to 2026
$3.0MRole of brain lipid metabolism in Alzheimer's diseaseR01AG065240 · NIA · CASE WESTERN RESERVE UNIVERSITY · PI QI, XIN · 2020 to 2024
$3.0MProteostasis dysregulation and alpha-synucleinR01NS115903 · NINDS · CASE WESTERN RESERVE UNIVERSITY · PI QI, XIN · 2020 to 2023
$2.4MBLRD VA I01 BX005976NCI NIH HHS P30 CA043703NIA NIH HHS F30 AG076183NIA NIH HHS P30 AG072977NIA NIH HHS R01 AG059721NIA NIH HHS R01 AG062566NIA NIH HHS R01 AG065240NIA NIH HHS R01 AG066707NIA NIH HHS R01 AG067741NIA NIH HHS R01 AG071512NIA NIH HHS R01 AG076051NIA NIH HHS R21 AG073684NIA NIH HHS RF1 AG074346NIA NIH HHS T32 AG071474NIA NIH HHS U01 AG073323NIDA NIH HHS P50 DA044123NIGMS NIH HHS RM1 GM142002NIGMS NIH HHS T32 GM007250NIGMS NIH HHS T32 GM152319NINDS NIH HHS R01 NS115903NINDS NIH HHS R01 NS122218NINDS NIH HHS RF1 NS122218NINDS NIH HHS T32 NS077888
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.
Indexed as
Brain Injuries, TraumaticDynaminsMitochondriaMitochondrial DynamicsMitochondrial ProteinsAnimalsBlood-Brain BarrierBrainChronic DiseaseDisease Models, AnimalHumansMaleMembrane ProteinsMiceMice, Inbred C57BLMicrogliaDnm1l protein, mouseDynaminsFIS1 protein, mouseMembrane ProteinsMitochondrial Proteinsblood-brain barrierDrp1Fis1mitochondriamitochondrial fissionmitochondrial fusionneurodegenerationneuroprotectionoxidative stresstraumatic brain injury
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