Modulation of miR-34a/SIRT1 signaling protects cochlear hair cells against oxidative stress and delays age-related hearing loss through coordinated regulation of mitophagy and mitochondrial biogenesis

• Published in: Neurobiology of aging 2019-07, Vol.79, p.30-42
• Main Authors: Xiong, Hao, Chen, Suijun, Lai, Lan, Yang, Haidi, Xu, Yaodong, Pang, Jiaqi, Su, Zhongwu, Lin, Hanqing, Zheng, Yiqing
• Format: Article
• Language: English
• Subjects: Aging; Animals; Cells, Cultured; Cochlea; Hair Cells, Auditory - metabolism; Hair Cells, Auditory - pathology; Hearing Loss, Sensorineural - etiology; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - prevention & control; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs - genetics; Mitochondria - genetics; Mitochondrial biogenesis; Mitophagy; Mitophagy - drug effects; Mitophagy - genetics; Organelle Biogenesis; Oxidative stress; Oxidative Stress - genetics; Presbycusis; Resveratrol - pharmacology; Signal Transduction; SIRT1; Sirtuin 1 - genetics
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2019.03.013

Mitophagy and mitochondrial biogenesis are 2 pathways that regulate mitochondrial content and metabolism maintaining cellular homeostasis. The imbalance between these opposing processes impairs mitochondrial function and is suggested to be the pathophysiological basis of a variety of neurodegenerative diseases and aging. Here we investigated the role of mitophagy and mitochondrial biogenesis in oxidative damage to the cochlear hair cells and age-related hearing loss. In cultured mouse House Ear Institute-Organ of Corti 1 hair cells, oxidative stress activated mitophagy but inhibited mitochondrial biogenesis and impaired mitochondrial function. Pharmacological inhibition of miR-34a/SIRT1 signaling enhanced mitophagy, mitochondrial biogenesis, and attenuated House Ear Institute-Organ of Corti 1 cell death induced by oxidative stress. In the cochlea of C57BL/6 mice, mitophagy and mitochondrial biogenesis were both upregulated during aging. Long-term supplementation with resveratrol, a SIRT1 activator, not only improved the balance between mitophagy and mitochondrial biogenesis but also significantly reduced age-related cochlear hair cell loss, spiral ganglion neuron loss, stria vascularis atrophy, and hearing threshold shifts in C57BL/6 mice. Moreover, SIRT1 overexpression or miR-34a deficiency both attenuated age-related cochlear hair cell loss and hearing loss in C57BL/6 mice. Our findings reveal that imbalance between mitophagy and mitochondrial biogenesis contributes to cochlea hair cell damage caused by oxidative stress and during aging. Coordinated regulation of these 2 processes by miR-34a/SIRT1 signaling might serve as a promising approach for the treatment of age-related cochlear degeneration and hearing loss. •Oxidative stress causes imbalance of mitochondrial homeostasis in HEI-OC1 cells.•miR-34a/SIRT1 modulates mitophagy and mitochondrial biogenesis in HEI-OC1 cells.•Imbalance of mitochondrial homeostasis is induced in aging cochlea.•miR-34a/SIRT1 protects cochlear hair cells by modulating mitochondrial homeostasis.•Activation of SIRT1 or inhibition of miR-34a delays age-related hearing loss.