title: Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness.
abstract: The A1555G mutation in the 12S rRNA gene of human mitochondrial DNA causes maternally inherited, nonsyndromic deafness, an extreme case of tissue-specific mitochondrial pathology. A transgenic mouse strain that robustly overexpresses the mitochondrial 12S ribosomal RNA methyltransferase TFB1M (Tg-mtTFB1 mice) exhibits progressive hearing loss that we proposed models aspects of A1555G-related pathology in humans. Although our previous studies of Tg-mtTFB1 mice implicated apoptosis in the spiral ganglion and stria vascularis because of mitochondrial reactive oxygen species-mediated activation of AMP kinase (AMPK) and the nuclear transcription factor E2F1, detailed auditory pathology was not delineated. Herein, we show that Tg-mtTFB1 mice have reduced endocochlear potential, indicative of significant stria vascularis dysfunction, but without obvious signs of strial atrophy. We also observed decreased auditory brainstem response peak 1 amplitude and prolonged wave I latency, consistent with apoptosis of spiral ganglion neurons. Although no major loss of hair cells was observed, there was a mild impairment of voltage-dependent electromotility of outer hair cells. On the basis of these results, we propose that these events conspire to produce the progressive hearing loss phenotype in Tg-mtTFB1 mice. Finally, genetically reducing AMPK α1 rescues hearing loss in Tg-mtTFB1 mice, confirming that aberrant up-regulation of AMPK signaling promotes the observed auditory pathology. The relevance of these findings to human A1555G patients and the potential therapeutic value of reducing AMPK activity are discussed.
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut; Department of Psychology, University of Bridgeport, Bridgeport, Connecticut.
authors.forename: Sharen E
authors.initials: SE
authors.lastname: McKay
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Wayne
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nouws
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Thormann
authors.affiliation: Institute of Cell Biology, University Medical Center Göettingen, Göttingen, Germany.
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Abdul
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut. Electronic address: joseph.santos-sacchi@yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Santos-Sacchi
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, Connecticut. Electronic address: lei.song@yale.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut. Electronic address: gerald.shadel@yale.edu.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics; D003638:Deafness / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D006199:Hair Cells, Auditory, Inner / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation; D009925:Organ of Corti / Q000473:pathology; D011930:Reaction Time / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013136:Spiral Ganglion / Q000473:pathology / Q000503:physiopathology; D013316:Stria Vascularis / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C462441:Tfb1m protein, mouse; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases