The effect of overexpression of PGC-1α on the mtDNA4834 common deletion in a rat cochlear marginal cell senescence model

• Published in: Hearing research Vol. 296; pp. 13 - 24
• Main Authors: Zhao, Xue-Yan, Sun, Jin-Li, Hu, Yu-Juan, Yang, Yang, Zhang, Wen-Juan, Hu, Yuan, Li, Jun, Sun, Yu, Zhong, Yi, Peng, Wei, Zhang, Hong-Lian, Kong, Wei-Jia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2013
• Subjects: Adenoviridae - genetics; Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Cellular Senescence - drug effects; Cellular Senescence - genetics; Cochlea - drug effects; Cochlea - metabolism; Cochlea - pathology; DNA, Mitochondrial - genetics; Dose-Response Relationship, Drug; Galactose - pharmacology; Genetic Predisposition to Disease; Genetic Vectors; NF-kappa B - metabolism; Nuclear Respiratory Factor 1 - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phenotype; Presbycusis - genetics; Presbycusis - metabolism; Presbycusis - pathology; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Sequence Deletion; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Up-Regulation; CD; NF-κB; SA-β-gal; LSCM; TUNEL; AHL; NRF-1; Tfam; PGC-1α; EP; MCs
• ISSN: 0378-5955; 1878-5891; 1878-5891
• DOI: 10.1016/j.heares.2012.11.007

Aging is a natural process usually defined as a progressive loss of function with an accumulation of senescent cells. The clinical manifestations of this process include age-related hearing loss (AHL)/presbycusis. Several investigations indicated the association between a mitochondrial common deletion (CD) (mtDNA 4977-bp deletion in humans, corresponding to 4834-bp deletion in rats) and presbycusis. Previous researches have shown that peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a key regulator of mitochondrial biogenesis and energy metabolism. However, the expression of PGC-1α in the inner ear and the possible effect of PGC-1α on presbycusis are not clear. Our data demonstrated the distribution of PGC-1α and its downstream transcription factors nuclear respiratory factor-1 (NRF-1), mitochondrial transcription factor A (Tfam) and nuclear factor κB (NF-κB) in marginal cells (MCs) for the first time. To explore the role of PGC-1α in cellular senescence, we established a model of marginal cell senescence harboring the mtDNA4834 common deletion induced by d-galactose. We also found that PGC-1α and its downstream transcription factors compensatorily increased in our cell senescence model. Furthermore, the overexpression of PGC-1α induced by transfection largely increased the expression levels of NRF-1 and TFAM and significantly decreased the expression level of NF-κB in the cell senescence model. And the levels of CD, senescent cells and apoptotic cells in the cell model decreased after PGC-1α overexpression. These results suggested that PGC-1α might protect MCs in this cell model from senescence through a nuclear-mitochondrial interaction and against apoptosis. Our study may shed light on the pathogenesis of presbycusis and provide a new therapeutic target for presbycusis. ► We established a rat marginal cells (MCs) senescence model with common deletion. ► PGC-1α and its downstream factors expressed in MCs. ► Nuclear-mitochondrial interaction played an important role in presbycusis. ► PGC-1α overexpression could protect MCs with common deletion from cellular senescence.