Activation of miR-34a impairs autophagic flux and promotes cochlear cell death via repressing ATG9A: implications for age-related hearing loss

Cell Death Dis. 2017 Oct 5;8(10):e3079. doi: 10.1038/cddis.2017.462.

Abstract

Age-related hearing loss is a major unresolved public health problem. We have previously elucidated that the activation of cochlear miR-34a is correlated with age-related hearing loss in C57BL/6 mice. A growing body of evidence points that aberrant autophagy promotes cell death during the development of multiple age-related diseases. The aim of this study was to investigate the role of miR-34a-involved disorder of autophagy in the pathogenesis of age-related hearing loss. Our results showed that miR-34a expression was markedly upregulated in the aging cochlea accompanied with impairment of autophagic flux. In the inner ear HEI-OC1 cell line, miR-34a overexpression resulted in an accumulation of phagophores and impaired autophagosome-lysosome fusion, and led to cell death subsequently. Notably, autophagy-related protein 9A (ATG9A), an autophagy protein, was significantly decreased after miR-34a overexpression. Knockdown of ATG9A inhibited autophagy flux, which is similar to the effects of miR-34a overexpression. Moreover, ursodeoxycholic acid significantly rescued miR-34a-induced HEI-OC1 cell death by restoring autophagy activity. Collectively, these findings increase our understanding of the biological effects of miR-34a in the development of age-related hearing loss and highlight miR-34a as a promising therapeutic target for its treatment.

MeSH terms

  • Aging / genetics*
  • Aging / pathology
  • Animals
  • Autophagy / genetics
  • Autophagy-Related Proteins / genetics*
  • Cell Line
  • Cochlea / metabolism
  • Cochlea / pathology
  • Disease Models, Animal
  • Gene Expression Regulation
  • Hearing Loss / genetics*
  • Hearing Loss / physiopathology
  • Humans
  • Membrane Proteins / genetics*
  • Mice
  • MicroRNAs / genetics*
  • Vesicular Transport Proteins / genetics*

Substances

  • Atg9A protein, mouse
  • Autophagy-Related Proteins
  • MIRN34a microRNA, mouse
  • Membrane Proteins
  • MicroRNAs
  • Vesicular Transport Proteins