MicroRNA-338 inhibition protects against focal cerebral ischemia and preserves mitochondrial function in vitro in astrocytes and neurons via COX4I1
| Autor: | Creed M. Stary, Ludmila A. Voloboueva, Brian B. Griffiths, Lijun Xu, Rona G. Giffard, L Li |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Small interfering RNA Programmed cell death Cell type Cell Survival Primary Cell Culture Ischemia Oxidative phosphorylation Article Brain Ischemia Electron Transport Complex IV 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Molecular Biology Cells Cultured Neurons Chemistry Cell Biology medicine.disease Cell biology Mitochondria Mice Inbred C57BL COX4I1 Disease Models Animal MicroRNAs 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Cell culture Astrocytes Molecular Medicine 030217 neurology & neurosurgery Astrocyte |
| Zdroj: | Mitochondrion |
| ISSN: | 1872-8278 |
| Popis: | Brain-enriched microRNA-338 (miR-338) is known to play a central role in brain mitochondrial function, however the role of miR-338 in stroke injury remains unknown. This study investigated the role of miR-338 in injury from transient focal cerebral ischemia in mice, and in cell survival and mitochondrial function after in vitro ischemia in astrocyte and neuronal cultures. Pre-treatment of mice with intracerebroventricular injection of miR-338 antagomir 24 h prior to 1 h of middle cerebral artery occlusion (MCAO) significantly reduced infarct size and improved neurological score at both 24 h and 7d after injury. Levels of the miR-338 target cytochrome-c oxidase subunit 4I1 (COX4I1), which plays an essential role in maintaining brain mitochondrial ATP production, were increased in miR-338 antagomir-treated mice. Mouse primary astrocyte cell cultures subjected to glucose deprivation exhibited increased cell survival when pre-treated with miR-338 inhibitor, and greater cell death with miR-338 mimic. Decreased miR-338 levels were associated with increased ATP production, augmented cytochrome c oxidative (CcO) activity and preservation of COX4I1. In vitro protection with miR-338 inhibitor was blocked by concurrent knockdown of COX4I1 with small interfering RNA. Parallel studies in mouse neuronal N2a cultures resulted in preserved ATP content and CcO activity with miR-338 inhibition, indicating a shared miR-338-dependent response to ischemic stress between brain cell types. These results suggest that miR-338 inhibition and/or COX4I1-targeted therapies may be novel clinical strategies to protect against stroke injury via preservation of mitochondrial function in multiple cell types. |
| Databáze: | OpenAIRE |
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