Jeong 2017 Exp Mol Med

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Jeong JH, Cheol Kang Y, Piao Y, Kang S, Pak YK (2017) miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway. Exp Mol Med 49:e313.

» PMID: 28386126 Open Access

Jeong JH, Cheol Kang Y, Piao Y, Kang S, Pak YK (2017) Exp Mol Med

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.

Keywords: SK-Hep1 human hepatoma cells Bioblast editor: Kandolf G O2k-Network Lab: KR Seoul Pak YK

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Human  Tissue;cell: Liver  Preparation: Permeabilized cells 

Coupling state: OXPHOS  Pathway: N, S, Gp, CIV, ROX  HRR: Oxygraph-2k