miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway
Experimental & Molecular Medicine
; : e313-2017.
Article
em En
| WPRIM
| ID: wpr-212085
Biblioteca responsável:
WPRO
ABSTRACT
Mitochondrial deficits or altered expressions of microRNAs are associated with the pathogenesis of various diseases, and microRNA-operated control of mitochondrial activity has been reported. Using a retrovirus-mediated short-hairpin RNA (shRNA) system, we observed that miR-24-mediated H2AX knockdown (H2AX-KD) impaired both mitochondria and the insulin signaling pathway. The overexpression of miR-24 decreased mitochondrial H2AX and disrupted mitochondrial function, as indicated by the ATP content, membrane potential and oxygen consumption. Similar mitochondrial damage was observed in shH2AX-mediated specific H2AX-KD cells. The H2AX-KD reduced the expression levels of mitochondrial transcription factor A (TFAM) and mitochondrial DNA-dependent transcripts. H2AX-KD mitochondria were swollen, and their cristae were destroyed. H2AX-KD also blocked the import of precursor proteins into mitochondria and the insulin-stimulated phosphorylation of IRS-1 (Y632) and Akt (S473 and T308). The rescue of H2AX, but not the nuclear form of ΔC24-H2AX, restored all features of miR-24- or shH2AX-mediated impairment of mitochondria. Hepatic miR-24 levels were significantly increased in db/db and ob/ob mice. A strong feedback loop may be present among miR-24, H2AX, mitochondria and the insulin signaling pathway. Our findings suggest that H2AX-targeting miR-24 may be a novel negative regulator of mitochondrial function and is implicated in the pathogenesis of insulin resistance.
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Índice:
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Assunto principal:
Consumo de Oxigênio
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Fosforilação
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Fatores de Transcrição
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Resistência à Insulina
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RNA
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Trifosfato de Adenosina
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MicroRNAs
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Insulina
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Potenciais da Membrana
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Mitocôndrias
Limite:
Animals
Idioma:
En
Revista:
Experimental & Molecular Medicine
Ano de publicação:
2017
Tipo de documento:
Article