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MicroRNA-210 Downregulates ISCU and Induces Mitochondrial Dysfunction and Neuronal Death in Neonatal Hypoxic-Ischemic Brain Injury

  • Qingyi MaEmail author
  • Chiranjib Dasgupta
  • Yong Li
  • Lei Huang
  • Lubo ZhangEmail author
Article
  • 103 Downloads

Abstract

Neonatal hypoxic-ischemic (HI) brain injury causes significant mortality and long-term neurologic sequelae. We previously demonstrated that HI significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of brain endogenous miR-210 was neuroprotective in HI brain injury. However, the molecular mechanisms underpinning this neuroprotection remain unclear. Using both in vivo and in vitro models, herein we uncover a novel mechanism mediating oxidative brain injury after neonatal HI, in which miR-210 induces mitochondrial dysfunction via downregulation of iron-sulfur cluster assembly protein (ISCU). Inhibition of miR-210 significantly ameliorates mitochondrial dysfunction, oxidative stress, and neuronal loss in the neonatal brain subjected to HI, as well as in primary cortical neurons exposed to oxygen-glucose deprivation (OGD). These effects are mediated through ISCU, in that miR-210 mimic decreases ISCU abundance in the brains of rat pups and primary cortical neurons, and inhibition of miR-210 protects ISCU against HI in vivo or OGD in vitro. Deletion of miR-210 binding sequences at the 3′UTR of ISCU transcript ablates miR-210-induced downregulation of ISCU protein abundance in PC12 cells. In primary cortical neurons, miR-210 mimic or silencing ISCU results in mitochondrial dysfunction, reactive oxygen species production, and activation of caspase-dependent death pathways. Of importance, knockdown of ISCU increases HI-induced injury in the neonatal rat brain and counteracts the neuroprotection of miR-210 inhibition. Therefore, miR-210 by downregulating ISCU and inducing mitochondrial dysfunction in neurons is a potent contributor of oxidative brain injury after neonatal HI.

Keywords

Neonatal hypoxia-ischemia MicroRNA-210 Mitochondrial dysfunction Oxidative stress Neuronal death 

Notes

Author Contributions

Q.M. and L.Z. contributed to the study design, manuscript preparation, and drafting the manuscript. Q.M., C.D., Y.L., and L.H. contributed to experiment conducting, and data collection and analysis. All authors read and approved the final manuscript.

Funding Information

This work was supported by the National Institutes of Health grants HL118861 and NS103017 to L.Z., and American Heart Association Western States Affiliate winter 2015 Beginning Grant-in-Aid 15BGIA25750063 to Q.M.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.The Lawrence D. Longo Center for Perinatal Biology, Department of Basic SciencesLoma Linda University School of MedicineLoma LindaUSA

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