TY - JOUR
T1 - Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury
AU - Sridharan, Preethy S.
AU - Koh, Yeojung
AU - Miller, Emiko
AU - Hu, Di
AU - Chakraborty, Suwarna
AU - Tripathi, Sunil Jamuna
AU - Kee, Teresa R.
AU - Chaubey, Kalyani
AU - Vázquez-Rosa, Edwin
AU - Barker, Sarah
AU - Liu, Hui
AU - León-Alvarado, Rose A.
AU - Franke, Kathryn
AU - Cintrón-Pérez, Coral J.
AU - Dhar, Matasha
AU - Shin, Min Kyoo
AU - Flanagan, Margaret E.
AU - Castellani, Rudolph J.
AU - Gefen, Tamar
AU - Bykova, Marina
AU - Dou, Lijun
AU - Cheng, Feixiong
AU - Wilson, Brigid M.
AU - Fujioka, Hisashi
AU - Kang, David E.
AU - Woo, Jung A.A.
AU - Paul, Bindu D.
AU - Qi, Xin
AU - Pieper, Andrew A.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/9/17
Y1 - 2024/9/17
N2 - 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.
AB - 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.
KW - Drp1
KW - Fis1
KW - blood-brain barrier
KW - mitochondria
KW - mitochondrial fission
KW - mitochondrial fusion
KW - neurodegeneration
KW - neuroprotection
KW - oxidative stress
KW - traumatic brain injury
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UR - http://www.scopus.com/inward/citedby.url?scp=85204510946&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2024.101715
DO - 10.1016/j.xcrm.2024.101715
M3 - Article
C2 - 39241772
AN - SCOPUS:85204510946
SN - 2666-3791
VL - 5
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 9
M1 - 101715
ER -