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
| Autor: | Zhongwu Su, Haidi Yang, Suijun Chen, Yaodong Xu, Jiaqi Pang, Hao Xiong, Yiqing Zheng, Hanqing Lin, Lan Lai |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aging Hearing Loss Sensorineural Presbycusis Cellular homeostasis Mice Transgenic Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Sirtuin 1 Hair Cells Auditory Mitophagy otorhinolaryngologic diseases medicine Animals Cells Cultured Cochlea Spiral ganglion Organelle Biogenesis General Neuroscience medicine.disease Mitochondria Cell biology Mice Inbred C57BL MicroRNAs Oxidative Stress 030104 developmental biology medicine.anatomical_structure Mitochondrial biogenesis Resveratrol sense organs Neurology (clinical) Hair cell Geriatrics and Gerontology 030217 neurology & neurosurgery Oxidative stress Signal Transduction Developmental Biology |
| Zdroj: | Neurobiology of Aging. 79:30-42 |
| ISSN: | 0197-4580 |
| DOI: | 10.1016/j.neurobiolaging.2019.03.013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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