TY - JOUR
T1 - Succinate Activates Uncoupling Protein 2 to Suppress Neuroinflammation and Confer Protection Following Intracerebral Hemorrhage
AU - Wang, Yecheng
AU - Huang, Caiyun
AU - Wang, Xiaoying
AU - Cheng, Rong
AU - Li, Xue
AU - Wang, Jiahao
AU - Zhang, Lu
AU - Li, Fuhao
AU - Wang, Hao
AU - Li, Xinyu
AU - Li, Yi
AU - Xia, Yiqing
AU - Cheng, Jian
AU - Pan, Xiaofan
AU - Jia, Jia
AU - Xiao, Guo Dong
N1 - Publisher Copyright:
Copyright 2024, Mary Ann Liebert, Inc., publishers.
PY - 2024
Y1 - 2024
N2 - Aims: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. Results: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, the oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxides, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophages, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream 5′-adenosine monophosphate-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I, or AMPK abolished the therapeutic effects of succinate following ICH. Innovation and Conclusion: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate-mediated intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate.
AB - Aims: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. Results: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, the oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxides, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophages, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream 5′-adenosine monophosphate-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I, or AMPK abolished the therapeutic effects of succinate following ICH. Innovation and Conclusion: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate-mediated intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate.
KW - intracerebral hemorrhage
KW - microglia
KW - neuroinflammation
KW - succinate
KW - uncoupling protein 2
UR - http://www.scopus.com/inward/record.url?scp=85205922118&partnerID=8YFLogxK
U2 - 10.1089/ars.2024.0573
DO - 10.1089/ars.2024.0573
M3 - Article
C2 - 39228046
AN - SCOPUS:85205922118
SN - 1523-0864
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
ER -