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.
Neurobiol Aging
; 79: 30-42, 2019 07.
Article
em En
| MEDLINE
| ID: mdl-31026620
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
1_ASSA2030
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6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Biogênese de Organelas
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Transdução de Sinais
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Estresse Oxidativo
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Mitofagia
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Células Ciliadas Auditivas
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Perda Auditiva Neurossensorial
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Mitocôndrias
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Neurobiol Aging
Ano de publicação:
2019
Tipo de documento:
Article