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

• Published in: Experimental & molecular medicine 2017-04, Vol.49 (4), p.e313-e313
• Main Authors: Jeong, Jae Hoon, Cheol Kang, Young, Piao, Ying, Kang, Sora, Pak, Youngmi Kim
• Format: Article
• Language: English
• Subjects: 13/109; 13/89; 14/19; 14/28; 38/35; 38/89; 38/90; 631/80/304; 631/80/642/333; 64/60; 96/34; 96/35; Adenosine Triphosphate - metabolism; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Cell Respiration; Gene Silencing; Histones - genetics; Histones - metabolism; Humans; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Medical Biochemistry; MicroRNAs - genetics; MicroRNAs - metabolism; Mitochondria - metabolism; Molecular Medicine; Original; original-article; Signal Transduction; Stem Cells
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2016.174

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. Insulin resistance: Investigating mitochondrial dysfunction The over-expression of a key protein regulator disrupts energy production in cells, potentially triggering insulin resistance. Defects in the functioning of mitochondria, cell components that produce energy, have been linked to degenerative diseases including insulin resistance and its associated condition, diabetes. Youngmi Kim Pak and co-workers at Kyung Hee University in Seoul, Republic of Korea, examined the interplay between a key protein found in mitochondrial membranes, H2AX, and its regulator molecule, a microRNA called miR-24. They found that H2AX plays an important role importing proteins into mitochondria, but when miR-24 is over-expressed the levels of H2AX in mitochondrial membranes are depleted. This blocks the import of mitochondrial proteins and impairs the correct functioning of insulin. Both miR-24 and H2AX may prove valuable as therapeutic targets for degenerative diseases.