Nur77 promotes cerebral ischemia–reperfusion injury via activating INF2-mediated mitochondrial fragmentation
Mitochondrial fragmentation drastically regulates mitochondrial homeostasis in brain illness. However, the role of mitochondrial fragmentation in cerebral ischemia–reperfusion (IR) injury remains unclear. Nur77, a regulator of mitochondrial homeostasis, is associated with heart and liver IR injury, but its effects on mitochondrial function in cerebral IR injury has not been studied intensively. The aim of our study is to explore whether cerebral IR injury is modulated by Nur77 via modification of mitochondrial homeostasis. Our results indicated that Nur77 was upregulated in reperfused brain tissues. Genetic ablation of Nur77 reduced infarction area and promoted neuron survival under IR burden. Biochemical analysis demonstrated that Nur77 deletion protected mitochondrial function, attenuated mitochondrial oxidative stress, preserved mitochondrial potential, and blocked mitochondria-related cell apoptosis. In addition, we illustrated that Nur77 mediated mitochondrial damage via evoking mitochondrial fragmentation that occurred through increased mitochondrial fission and decreased fusion. Besides, our results also demonstrated that Nur77 controlled mitochondrial fragmentation via upregulating INF2 in a manner dependent on the Wnt/β-catenin pathway; inhibition of the Wnt pathway abrogated the protective effect of Nur77 deletion on reperfused-mediated neurons. Altogether, our study highlights that the pathogenesis of cerebral IR injury is associated with Nur77 activation followed by augmented mitochondrial fragmentation via an abnormal Wnt/β-catenin/INF2 pathway. Accordingly, Nur77-dependent mitochondrial fragmentation and the Wnt/β-catenin/INF2 axis may represent novel therapeutic targets to reduce cerebral IR injury.
KeywordsStroke Nur77 Cerebral IR injury Wnt/β-catenin/INF2 axis Mitochondrial fragmentation
Thanks to Dr. Zhenhai Zhang, Dr. Chunsen Shen and Dr. Yunjun Li. Due to the personal reason, these authors have left from PLA army general hospital and are working in Xiangya hospital. According to their request and their new hospital policy, they ask to remove their name from the original submission. All the authors have approved this decision. Thanks for their contributions to this work.
HZ, YCL, and LHC conceived the research; WLP, HZ and RXX performed the experiments; all authors participated in discussing and revising the manuscript.
This study was supported by a grant from the National Natural Science Foundation of China (Grant No. 81100917) and Beijing Nova program (Z171100001117096).
Compliance with ethical standards
Conflict of interest
The authors have declared that they have no conflicts of interest.
Ethics approval and consent to participate
The animal study was performed in accordance with the Declaration of Helsinki. All experimental protocols were approved by the Ethics Committee of Department of neurosurgery, PLA army general hospital, Beijing, China, Beijing, China. The ethics reference number: SCSSJN20112.
- Fan J et al (2017) Therapeutic hypothermia attenuates global cerebral reperfusion-induced mitochondrial damage by suppressing dynamin-related protein 1 activation and mitochondria-mediated apoptosis in a cardiac arrest rat model. Neurosci Lett 647:45–52. https://doi.org/10.1016/j.neulet.2017.02.065 CrossRefPubMedGoogle Scholar
- Jokinen R, Pirnes-Karhu S, Pietilainen KH, Pirinen E (2017) Adipose tissue NAD(+)-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health. Redox Biol 12:246–263. https://doi.org/10.1016/j.redox.2017.02.011 CrossRefPubMedPubMedCentralGoogle Scholar
- Kang Z, Zhu H, Luan H, Han F, Jiang W (2014) Curculigoside A induces angiogenesis through VCAM-1/Egr-3/CREB/VEGF signaling pathway. Neuroscience 267:232–240. https://doi.org/10.1016/j.neuroscience.2014.02.050 CrossRefPubMedGoogle Scholar
- Li R, Xin T, Li D, Wang C, Zhu H, Zhou H (2018) Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol 18:229–243. https://doi.org/10.1016/j.redox.2018.07.011 CrossRefPubMedPubMedCentralGoogle Scholar
- Nauta TD, van den Broek M, Gibbs S, van der Pouw-Kraan TC, Oudejans CB, van Hinsbergh VW, Koolwijk P (2017) Identification of HIF-2alpha-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis 20:39–54. https://doi.org/10.1007/s10456-016-9527-4 CrossRefPubMedGoogle Scholar
- Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A (2017) Reverse electron transfer results in a loss of flavin from mitochondrial complex I: potential mechanism for brain ischemia reperfusion injury. J Cereb Blood Flow Metab 37:3649–3658. https://doi.org/10.1177/0271678X17730242 CrossRefPubMedGoogle Scholar
- Zhou H et al (2017) Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J Am Heart Assoc. https://doi.org/10.1161/JAHA.116.005328 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y (2018c) BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis 21:599–615. https://doi.org/10.1007/s10456-018-9611-z CrossRefPubMedPubMedCentralGoogle Scholar