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

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.

Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss

“…We hypothesized that mitochondrial dysfunction was induced by a disturbance in mitophagy. Our previous study revealed that rapamycin can preserve mitochondrial function by initiating autophagy (Pang et al, 2017). We found that in cellular senescence, the disturbed autophagy flux assessed by the LC3 II and P62 proteins confirmed our hypothesis.…”

“…Auditory brainstem response (ABR) tests were conducted using the Tucker-Davis Technology (TDT) System III (Alachua, FL, USA) as previously described (Pang et al, 2017). In brief, mice were anesthetized, and subdermal needle electrodes were inserted at the vertex (active) and below the left ear (reference) and the right ear (ground).…”

“…Western Blotting was conducted as previously described (Pang et al, 2017). Briefly, proteins were extracted from cells and cochlea tissues using radioimmunoprecipitation assay lysis buffer (Thermo plus, USA).…”

Presbycusis: An Update on Cochlear Mechanisms and Therapies

“…It has been reported that miR-34a, which has been implicated in inducing senescence, cell cycle arrest, autophagy, and cell death [96], is also linked to ARHL in c57BL/6 mice [97]. In addition, upregulation of miR-34a in the aging cochlea was accompanied by impairment of autophagic flux, with an accumulation of phagophores and impaired autophagosome-lysosome fusion [98]. Together, these results suggest that autophagy may be a housekeeping mechanism necessary for cochlear cell survival during aging.…”

Peer Review #2 of "Cmah deficiency may lead to age-related hearing loss by influencing miRNA-PPAR mediated signaling pathway (v0.1)"

“…MicroRNAs (miRNAs) are a class of small RNAs (18-25-nucleotide) that down-regulate the expression of target genes via binding to the 3′-untranslated region (UTR) and then participate in the cellular processes. There has been evidence to indicate miRNAs participate in the pathogenesis of AHL, including miR-34a (Huang et al 2017;Pang et al 2017)…”