DUSP1 alleviates cerebral ischaemia reperfusion injury via inactivating JNK-Mff pathways and repressing mitochondrial fission.
Life Sci
; 210: 251-262, 2018 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-30138595
ABSTRACT
AIMS:
Evidence continues to accrue implicating mitochondrial fission in the aetiology of cerebral ischaemia reperfusion (IR) injury. Dual-specificity phosphatase-1 (DUSP1) has been found to be associated with mitochondrial protection in several diseases. We aimed to explore the functional role of DUSP1 in cerebral IR injury, focusing on its influence on mitochondrial fission. MAINMETHODS:
WT mice and DUSP1 transgenic mice were subjected to cerebral IR in vivo. In vitro, the hypoxia-reoxygenation model was used with N2a cells to mimic cerebral IR injury. Mitochondrial function was monitored via western blotting and immunofluorescence. Pathway blocker was used to establish the role of the JNK-Mff signaling pathway in mitochondrial fission. KEYFINDINGS:
DUSP1 expression is downregulated after cerebral IR injury, and overexpression of DUSP1 could significantly reduce the infarction area and attenuate neuronal death exerted by cerebral IR injury. In vitro, we found that HR injury induced neuronal mitochondrial damage via augmenting mitochondrial fission. DUSP1 overexpression inhibited mitochondrial fission, thereby preserving mitochondrial homeostasis against HR injury. Furthermore, our data illustrated that DUSP1 regulated mitochondrial fission via JNK-Mff pathways. Increased DUSP1 prevented JNK activation, upregulated Yap expression, and suppressed Mff phosphorylation, reducing the formation of mitochondrial fragmentation. However, re-activation of JNK-Mff pathways abrogated the inhibitory effect of DUSP1 overexpression on mitochondrial fission.SIGNIFICANCE:
This finding first uncovers that DUSP1 downregulation could be considered the primary reason for cerebral IR injury via evoking deleterious mitochondrial fission and activating harmful JNK-Mff pathways.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Daño por Reperfusión
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Isquemia Encefálica
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Proteínas Mitocondriales
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MAP Quinasa Quinasa 4
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Fosfatasa 1 de Especificidad Dual
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Proteínas de la Membrana
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Mitocondrias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Life Sci
Año:
2018
Tipo del documento:
Article
País de afiliación:
China