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

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 BykovaLijun Dou, Feixiong Cheng, Brigid M. Wilson, Hisashi Fujioka, David E. Kang, Jung A.A. Woo, Bindu D. Paul, Xin Qi^*, Andrew A. Pieper^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	101715
Journal	Cell Reports Medicine
Volume	5
Issue number	9
DOIs	https://doi.org/10.1016/j.xcrm.2024.101715
State	Published - Sep 17 2024

Funding

A.A.P. was supported by the Valour Foundation. A.A.P. was also supported as the Rebecca E. Barchas, MD, DLFAPA, University Professor in Translational Psychiatry of Case Western Reserve University and the Morley-Mather Chair in Neuropsychiatry of University Hospitals of Cleveland Medical Center. A.A.P. and B.D.P. were supported by the American Heart Association and Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment (19PABH134580006) and by NIH/NIA 1R01AG071512. A.A.P. also acknowledges support from the Department of Veterans Affairs Merit Award I01BX005976, NIH/NIGMS RM1 GM142002, NIH/NIA RO1AG066707, NIH/NIA 1 U01 AG073323, the Louis Stokes VA Medical Center resources and facilities, the Wick Foundation, and the Meisel & Pesses Family Foundation. X.Q. was supported by NIH/NIA RO1AG065240, NIH/NIA RF1AG074346, NIH/NIA R01AG076051, and NIH/NINDS R01NS115903. B.D.P. was supported by NIH NIDA grant P50 DA044123, NIH 1R21AG073684-01, and the Catalyst Award from Johns Hopkins University. D.E.K. and J.-A.A.W. were supported by NIH/NIA 1R01AG067741-01 and NIH/NINDS 1R01NS122218-A1. R.A.L.-A. was supported by the American Heart Association SURE Scholar Program. S.B. and E.M. were supported by the Alzheimer's Disease Translational Data Science Training Program NIH T32 AGO71474. E.V.-R. was supported by Department of Defense Peer-Reviewed Alzheimer's Research Program (PRARP) Award AZ210092 (W81XWH-22-1-0129). P.S.S. was supported by NIH/NIA F30AG076183 and NIH/NINDS T32NS077888. P.S.S. and S.B. were supported by Case Western Medical Scientist Training program NIH T32 GM007250. Y.K. was supported by NIH/NIA F99 AGO83111. M.-K.S. was supported by the New Faculty Startup Fund (370C-20220110), Creative-Pioneering Researchers Program (370C-20230108), and a research grant (370C-20240120) from Seoul National University. M.-K.S. also acknowledges support from the National Research Foundation of Korea (RS-2023-00209597, RS-2024-00352229) and donors of Alzheimer's Disease Research, a program of BrightFocus Foundation (A2019551F). M.E.F., R.J.C., and T.G. were supported by grants from the NIA (P30AG072977, R01AG062566). We also thank the Translational Research Shared Resource of the Case Comprehensive Cancer Center (NIH/NCI P30 CA43703) for the use of the Seahorse analyzer. We also acknowledge BioRender.com, a service we used to design our schematic figures. A.A.P. was supported by the Valour Foundation . A.A.P. was also supported as the Rebecca E. Barchas, MD, DLFAPA, University Professor in Translational Psychiatry of Case Western Reserve University and the Morley-Mather Chair in Neuropsychiatry of University Hospitals of Cleveland Medical Center. A.A.P. and B.D.P. were supported by the American Heart Association and Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment ( 19PABH134580006 ) and by NIH / NIA 1R01AG071512 . A.A.P. also acknowledges support from the Department of Veterans Affairs Merit Award I01BX005976 , NIH / NIGMS RM1 GM142002 , NIH / NIA RO1AG066707 , NIH / NIA 1 U01 AG073323 , the Louis Stokes VA Medical Center resources and facilities, the Wick Foundation, and the Meisel & Pesses Family Foundation . X.Q. was supported by NIH/NIA RO1AG065240 , NIH / NIA RF1AG074346 , NIH/NIA R01AG076051 , and NIH / NINDS R01NS115903 . B.D.P. was supported by NIH NIDA grant P50 DA044123 , NIH 1R21AG073684-01 , and the Catalyst Award from Johns Hopkins University . D.E.K. and J.-A.A.W. were supported by NIH / NIA 1R01AG067741-01 and NIH / NINDS 1R01NS122218-A1 . R.A.L.-A. was supported by the American Heart Association SURE Scholar Program . S.B. and E.M. were supported by the Alzheimer\u2019s Disease Translational Data Science Training Program NIH T32 AGO71474. E.V.-R. was supported by Department of Defense Peer-Reviewed Alzheimer\u2019s Research Program (PRARP) Award AZ210092 ( W81XWH-22-1-0129 ). P.S.S. was supported by NIH / NIA F30AG076183 and NIH / NINDS T32NS077888 . P.S.S. and S.B. were supported by Case Western Medical Scientist Training program NIH T32 GM007250 . Y.K. was supported by NIH/NIA F99 AGO83111. M.-K.S. was supported by the New Faculty Startup Fund (370C-20220110), Creative-Pioneering Researchers Program (370C-20230108), and a research grant (370C-20240120) from Seoul National University. M.-K.S. also acknowledges support from the National Research Foundation of Korea (RS-2023-00209597, RS-2024-00352229) and donors of Alzheimer\u2019s Disease Research, a program of BrightFocus Foundation (A2019551F). M.E.F., R.J.C., and T.G. were supported by grants from the NIA ( P30AG072977 , R01AG062566 ). We also thank the Translational Research Shared Resource of the Case Comprehensive Cancer Center ( NIH / NCI P30 CA43703 ) for the use of the Seahorse analyzer. We also acknowledge BioRender.com, a service we used to design our schematic figures.

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2024.101715

Cite this

Sridharan, P. S., Koh, Y., Miller, E., Hu, D., Chakraborty, S., Tripathi, S. J., Kee, T. R., Chaubey, K., Vázquez-Rosa, E., Barker, S., Liu, H., León-Alvarado, R. A., Franke, K., Cintrón-Pérez, C. J., Dhar, M., Shin, M. K., Flanagan, M. E., Castellani, R. J., Gefen, T., ... Pieper, A. A. (2024). Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury. Cell Reports Medicine, 5(9), Article 101715. https://doi.org/10.1016/j.xcrm.2024.101715

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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.",

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author = "Sridharan, {Preethy S.} and Yeojung Koh and Emiko Miller and Di Hu and Suwarna Chakraborty and Tripathi, {Sunil Jamuna} and Kee, {Teresa R.} and Kalyani Chaubey and Edwin V{\'a}zquez-Rosa and Sarah Barker and Hui Liu and Le{\'o}n-Alvarado, {Rose A.} and Kathryn Franke and Cintr{\'o}n-P{\'e}rez, {Coral J.} and Matasha Dhar and Shin, {Min Kyoo} and Flanagan, {Margaret E.} and Castellani, {Rudolph J.} and Tamar Gefen and Marina Bykova and Lijun Dou and Feixiong Cheng and Wilson, {Brigid M.} and Hisashi Fujioka and Kang, {David E.} and Woo, {Jung A.A.} and Paul, {Bindu D.} and Xin Qi and Pieper, {Andrew A.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

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doi = "10.1016/j.xcrm.2024.101715",

language = "English (US)",

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Sridharan, PS, Koh, Y, Miller, E, Hu, D, Chakraborty, S, Tripathi, SJ, Kee, TR, Chaubey, K, Vázquez-Rosa, E, Barker, S, Liu, H, León-Alvarado, RA, Franke, K, Cintrón-Pérez, CJ, Dhar, M, Shin, MK, Flanagan, ME, Castellani, RJ , Gefen, T, Bykova, M, Dou, L, Cheng, F, Wilson, BM, Fujioka, H, Kang, DE, Woo, JAA, Paul, BD, Qi, X & Pieper, AA 2024, 'Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury', Cell Reports Medicine, vol. 5, no. 9, 101715. https://doi.org/10.1016/j.xcrm.2024.101715

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AU - Tripathi, Sunil Jamuna

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

Abstract

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