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

Authors

Qingyi Ma, The Lawrence D. Longo Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.Follow
Chiranjib Dasgupta, The Lawrence D. Longo Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.Follow
Yong Li, The Lawrence D. Longo Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.Follow
Lei Huang, The Lawrence D. Longo Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.Follow
Lubo Zhang, The Lawrence D. Longo Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.Follow

Document Type

Article

Publication Date

8-1-2019

Publication Title

Molecular neurobiology

E-ISSN

1559-1182

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.

Volume

56

Issue

8

First Page

5608

Last Page

5625

DOI

10.1007/s12035-019-1491-8

PubMed ID

30656514

Recommended Citation

Ma, Qingyi; Dasgupta, Chiranjib; Li, Yong; Huang, Lei; and Zhang, Lubo, "MicroRNA-210 Downregulates ISCU and Induces Mitochondrial Dysfunction and Neuronal Death in Neonatal Hypoxic-Ischemic Brain Injury" (2019). Loma Linda University Faculty Publications. 328.
https://scholarsrepository.llu.edu/fac_pubs/328