Researchers at Yale School of Medicine have found that, for a mitochondrial defect that leads to hereditary hearing loss, manipulation of a certain enzyme may delay or prevent hearing loss.
Gerald S. Shadel, PhD, the lead investigator of a collaborative research team from Yale School of Medicine’s departments of Pathology, Genetics, Surgery, Cellular and Molecular Physiology, and Neurobiology, reports that mytochondrial dysfunction is responsible for a type of human hereditary deafness that worsens over time, leading to profound hearing loss. In a genetically-modified mouse model with a mitochondrial dysfunction that results in a similar premature hearing loss, Shadel and the research team showed that precise genetic reduction of an enzyme, AMP kinase (AMPK), can rescue the hearing. Their results are reported in an article in the November 6, 2015 edition of The American Journal of Pathology.
According to the authors, mitochondrial diseases are complicated and heterogeneous, characterized by cell- and tissue-specific responses and pathology. To study this particular type of maternally inherited deafness, Shadel and colleagues bred transgenic mice that over-express the gene encoding transcription factor B1, mitochondrial (TFB1M). The Tfb1m protein (aka mtTFB1) modifies the 12S ribosomal RNA of mitochondrial ribosomes that are necessary to express mtDNA-encoded genes. These Tg-mtTFB1 mice develop hearing loss at a very fast rate.
With co-investigator Joseph Santos-Sacchi, PhD, Shadel and the team compared anatomical and functional differences in the hearing pathways of the Tg-mtTFB1 mice. They observed multiple defects in the cochlea, including in the spiral ganglion nerves and the stria vascularis. “We propose that the defects we observed in the stria, spiral ganglion neurons, and outer hair cells conspire to produce the observed hearing loss profile in Tg-mtTFB1 mice,” said first author Sharen McKay, PhD, Department of Pathology, Yale School of Medicine and Department of Psychology, University of Bridgeport.
The researchers report that the pathway to hearing loss in the Tg-mtTFB1 mice is initiated by a mitochondrial reactive oxygen species that stimulates the enzyme AMPK, which then activates deleterious signaling events in specific parts of the inner ear. The investigators reasoned that reducing AMPK activity could prevent the hearing loss. To test this hypothesis, they bred Tg-mtTFB1 mice that had one of their AMPK genes knocked out. They found that the Tg-mtTFB1 group showed the expected indicators of hearing loss in young mice, while the Tg-mtTFB1 mice in which the AMPK gene was also knocked-out showed hearing thresholds indistinguishable from those of controls.
The researchers concluded that reducing AMPK signaling has no effect on normal hearing at the ages tested but rescues or delays premature hearing loss in Tg-mtTFB1 mitochondrial deafness model mice. They note that this opens the possibility for intervention in humans based on inhibiting AMPK, which is already a drug target for several diseases. The researchers emphasize that additional work is needed before the results from this mouse model are used to inform pathology in maternally inherited deafness in humans or to develop therapeutic strategies.
Source: Yale School of Medicine
Image credits: Yale School of Medicine; © Molekuul | Dreamstime.com (AMP-activated protein kinase (AMPK) fragment with AMP bound. AMPK regulates cellular metabolism depending on energy availability. Atoms shown as spheres. Coloring: per chain.)