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Am J Pathol. 2015 Dec;185(12):3132-40. doi: 10.1016/j.ajpath.2015.08.014. Epub 2015 Nov 6.

Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness.

Author information

1
Department of Pathology, Yale School of Medicine, New Haven, Connecticut; Department of Psychology, University of Bridgeport, Bridgeport, Connecticut.
2
Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
3
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
4
Institute of Cell Biology, University Medical Center Göettingen, Göttingen, Germany.
5
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.
6
Department of Surgery, Yale School of Medicine, New Haven, Connecticut. Electronic address: lei.song@yale.edu.
7
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.

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.

PMID:
26552864
DOI:
10.1016/j.ajpath.2015.08.014
[Indexed for MEDLINE]
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