MiR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway

Jae Hoon Jeong, Young Cheol Kang, Ying Piao, Sora Kang, Youngmi Kim Pak

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere313
JournalExperimental and Molecular Medicine
Volume49
Issue number4
DOIs
StatePublished - Apr 7 2017

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Mitochondria
Insulin
MicroRNAs
Phosphorylation
Protein Precursors
Retroviridae
Mitochondrial DNA
Oxygen Consumption
Membrane Potentials
Small Interfering RNA
Insulin Resistance
Adenosine Triphosphate
Oxygen
Membranes
Feedback
Liver

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

MiR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway. / Jeong, Jae Hoon; Cheol Kang, Young; Piao, Ying; Kang, Sora; Pak, Youngmi Kim.

In: Experimental and Molecular Medicine, Vol. 49, No. 4, e313, 07.04.2017.

Research output: Contribution to journalArticle

Jeong, Jae Hoon ; Cheol Kang, Young ; Piao, Ying ; Kang, Sora ; Pak, Youngmi Kim. / MiR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway. In: Experimental and Molecular Medicine. 2017 ; Vol. 49, No. 4.
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