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.

Hearing consequences in Gjb2 knock-in mice: implications for human p.V37I mutation

“…Gene therapy has recently gained successes in treating various kinds of deafness [33, 113–118]. With the advances in gene therapy delivery and safety such as base editing [27, 119, 120] and improved encapsulation via nanoparticles or hydrogels [121–123], we are optimistic that treatment options for patients will become more available in the not too distant future. Meanwhile, chemicals that target the potassium channel activity also remain a promising therapeutic approach to reduce or delay the disease progression.…”

Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis

“…In addition to activation of autophagosome formation, AMPK stimulates both mitochondrial and lysosomal biogenesis [11][12][13]. Persistent activation of AMPK can, however, trigger apoptosis in vitro and in vivo [14][15][16]. The metabolic and signaling roles of AMPK place it at the crossroads between mitochondrial function and autophagy.…”

Mitochondrial adventures at the organelle society

“…While undoubtedly correct, the designation “energy factory” for mitochondria is simplistic and incomplete. In addition, mitochondria are major Ca 2+ stores, assembly lines for Fe-S and participants in the synthesis of many other cellular components, and are nowadays recognized as key signaling platforms impacting fundamental processes such as cell division, differentiation, anti-viral signaling, autophagy and death [1] , [2] , [3] , [4] , [5] , [6] . The understanding of mitochondria as a signaling organelle started with the discovery that under certain challenges mitochondria release their Ca 2+ content, and was further solidified by the identification of mutations in mitochondrial DNA (mtDNA) as cause of disease [7] , [8] , and with the understanding that mitochondria communicate with the cellular signaling environment, regulating gene expression programs [9] .…”