A mitochondrial defect causes maternally inherited, nonsyndromic deafness, an extreme case of tissue-specific mitochondrial pathology. Now, in a study published in the American Journal of Pathology, a team of researchers using a transgenic mouse model with a mitochondrial defect that causes an analogous premature hearing loss discovered that a genetic reduction of the AMP kinase (AMPK) enzyme can prevent such deafness.
“Mitochondrial dysfunction causes human diseases, with an estimated occurrence of 1 in 5,000 to 10,000 live births. Mitochondrial diseases are complicated and heterogeneous, characterized by cell- and tissue-specific responses and pathology. An extreme example of tissue specificity is the A1555G mitochondrial DNA (mtDNA) mutation that causes maternally-inherited deafness,” explained the study’s lead investigator, Gerald S. Shadel, PhD, of the Departments of Pathology and Genetics at Yale School of Medicine, in a news release.
To investigate this specific form of deafness, in the study entitled “Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness,” the research team bred transgenic mouse strains over-expressing the gene that encodes the mitochondrial transcription factor B1 (mtTFB1), which is able to modify the 12S ribosomal RNA needed to express genes encoded in the human mitochondrial DNA, or mtDNA. These mtTFB1 transgenic mice acquire hearing loss much faster than wild-type mice controls.
The team of researchers of Dr. Shadel and Dr. Joseph Santos-Sacchi, from the Departments of Surgery, Cellular and Molecular Physiology, and Neurobiology at the Yale School of Medicine, compared the functional and anatomical differences in hearing pathways of the transgenic mice.
Researchers observed multiple defects in the mice cochlea, including in the stria vascularis and in the nerves of the spiral ganglion. “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,” noted Sharen McKay, PhD, Department of Pathology, Yale School of Medicine and Department of Psychology, University of Bridgeport, the first author of the study.
The team believes that the pathway to hearing loss in the transgenic mice is started by mitochondrial reactive oxygen species, which stimulate the AMPK enzyme that later triggers adverse signaling processes in specific inner ear parts. In the study, researchers thought that by reducing the activity of the AMPK enzyme, they could avoid hearing loss.
To assess this assumption, the team bred transgenic mice that were lacking one of their AMPK genes. Between 9 and 12 months of age, the transgenic group of mice exhibited an increase in the auditory brainstem response (ABR) threshold, which indicates hearing loss. In contrast, the transgenic mice in which the AMPK gene was also knocked-out had ABR thresholds similar to the controls.
“We conclude 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. This opens the possibility for intervention in humans based on inhibiting AMPK, which is already a drug target for several diseases,” stated Dr. Shadel.
Researchers noted that more studies are necessary before the findings derived from this specific transgenic mouse model can be applied in clinical practice in cases of maternally inherited deafness caused by mtDNA mutations, and to comprehend how the findings can lead to prophylactic strategies or therapeutic approaches.