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

doi:10.1016/j.xcrm.2024.101715

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

Cell Rep Med. 2024 Sep 17;5(9):101715. doi: 10.1016/j.xcrm.2024.101715. Epub 2024 Sep 5.

Authors

Preethy S Sridharan¹, Yeojung Koh², Emiko Miller¹, Di Hu³, Suwarna Chakraborty⁴, Sunil Jamuna Tripathi⁴, Teresa R Kee⁵, Kalyani Chaubey⁶, Edwin Vázquez-Rosa⁶, Sarah Barker², Hui Liu⁶, Rose A León-Alvarado⁷, Kathryn Franke⁶, Coral J Cintrón-Pérez⁶, Matasha Dhar⁶, Min-Kyoo Shin⁸, Margaret E Flanagan⁹, Rudolph J Castellani¹⁰, Tamar Gefen¹¹, Marina Bykova¹², Lijun Dou¹³, Feixiong Cheng¹³, Brigid M Wilson¹⁴, Hisashi Fujioka¹⁵, David E Kang¹⁶, Jung-A A Woo⁵, Bindu D Paul¹⁷, Xin Qi¹⁸, Andrew A Pieper¹⁹

Affiliations

¹ 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.
² 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.
³ Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
⁴ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Department of Regulatory Biology, Cleveland State University, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹³ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁴ Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Louis Stokes VA Medical Center, Cleveland, OH, USA.
¹⁵ Cryo-Electron Microscopy Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹⁶ 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.
¹⁷ 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.
¹⁸ Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address: [email protected].
¹⁹ 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: [email protected].

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.

Keywords: Drp1; Fis1; blood-brain barrier; mitochondria; mitochondrial fission; mitochondrial fusion; neurodegeneration; neuroprotection; oxidative stress; traumatic brain injury.

MeSH terms

Animals
Blood-Brain Barrier / metabolism
Blood-Brain Barrier / pathology
Brain / metabolism
Brain / pathology
Brain Injuries, Traumatic* / metabolism
Brain Injuries, Traumatic* / pathology
Chronic Disease
Disease Models, Animal
Dynamins* / genetics
Dynamins* / metabolism
Humans
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Microglia / metabolism
Microglia / pathology
Mitochondria* / metabolism
Mitochondrial Dynamics*
Mitochondrial Proteins* / genetics
Mitochondrial Proteins* / metabolism
Neurodegenerative Diseases / metabolism
Neurodegenerative Diseases / pathology
Oxidative Stress

Substances

Dynamins
Mitochondrial Proteins
FIS1 protein, mouse
Membrane Proteins
Dnm1l protein, mouse

Abstract

MeSH terms

Substances

Grants and funding