title: The effect of overexpression of PGC-1α on the mtDNA4834 common deletion in a rat cochlear marginal cell senescence model.
abstract: 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.
authors.affiliation: Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Zhao
authors.forename: Jin-Li
authors.initials: JL
authors.lastname: Sun
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Hu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Hong-Lian
authors.initials: HL
authors.lastname: Zhang
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005690:Galactose / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D016328:NF-kappa B / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D011304:Presbycusis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017384:Sequence Deletion; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D016328:NF-kappa B; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C489030:Tfam protein, rat; D014157:Transcription Factors; D005690:Galactose