title: Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness.
abstract: Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming from primary defects in respiration, coupled with altered reactive oxygen species (ROS), metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally inherited deafness disrupts mitochondrial ribosome function, in part, via increased methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patient-derived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent hearing loss. This mouse mitochondrial disease model provides a robust platform for deciphering the complex tissue specificity of human mitochondrial-based disorders, as well as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by environmental factors.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Shutt
authors.forename: Sharen E
authors.initials: SE
authors.lastname: McKay
authors.forename: Justin
authors.initials: J
authors.lastname: Cotney
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Gilliland
authors.forename: David
authors.initials: D
authors.lastname: Hohuan
authors.forename: Joseph
authors.initials: J
authors.lastname: Santos-Sacchi
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003638:Deafness / Q000378:metabolism*; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D007758:Ear, Inner / Q000473:pathology; D045888:Ganglion Cysts / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000473:pathology; D012335:RNA, Ribosomal / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D024101:Mitochondrial Proteins; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D017382:Reactive Oxygen Species; C499632:TFB1M protein, human; C462441:Tfb1m protein, mouse; D014157:Transcription Factors