title: Mitochondrial transcription factor A overexpression and base excision repair deficiency in the inner ear of rats with D-galactose-induced aging.
abstract: Oxidative damage to mtDNA is associated with excessive reactive oxygen species production. The mitochondrial common deletion (mtDNA 4977-bp and 4834-bp deletion in humans and rats, respectively) is the most typical and frequent form of mtDNA damage associated with aging and degenerative diseases. The accumulation of the mitochondrial common deletion has been proposed to play a crucial role in age-related hearing loss (presbycusis). However, the mechanisms underlying the formation and accumulation of mtDNA deletions are still obscure. In the present study, a rat mimetic aging model induced by D-Gal was used to explore the origin of deletion mutations and how mtDNA repair systems modulate this process in the inner ear during aging. We found that the mitochondrial common deletion was greatly increased and mitochondrial base excision repair capacity was significantly reduced in the inner ear in D-Gal-treated rats as compared with controls. The overexpression of mitochondrial transcription factor A induced by D-Gal significantly stimulated mtDNA replication, resulting in an increase in mtDNA copy number. In addition, an age-related loss of auditory sensory cells in the inner ear was observed in D-Gal-treated rats. Taken together, our data suggest that mitochondrial base excision repair capacity deficiency and an increase in mtDNA replication resulting from mitochondrial transcription factor A overexpression may contribute to the accumulation of mtDNA deletions in the inner ear during aging. This study also provides new insights into the development of presbycusis.
authors.affiliation: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Hu
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Zhao
authors.forename: Guo-run
authors.initials: GR
authors.lastname: Fan
authors.forename: Xiang
authors.initials: X
authors.lastname: Huang
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D007758:Ear, Inner / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005690:Galactose / Q000633:toxicity; D017353:Gene Deletion; D018628:Gene Dosage / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011304:Presbycusis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000378:metabolism; D000077278:RNA, Mitochondrial; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D000077278:RNA, Mitochondrial; C489030:Tfam protein, rat; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D012313:RNA; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D005690:Galactose