A mitochondrial defect is responsible for a type of human hereditary deafness that worsens over time and can lead to profound hearing loss. Reducing enzyme activity in mice with mitochondrial dysfunction prevents or delays deafness. [Darryl Leja, NHGRI]
A mitochondrial defect is responsible for a type of human hereditary deafness that worsens over time and can lead to profound hearing loss. Reducing enzyme activity in mice with mitochondrial dysfunction prevents or delays deafness. [Darryl Leja, NHGRI]

Mitochondrial diseases represent a collection of genetic disorders whose symptoms vary widely from muscle weakness and cardiac defects to blindness and dementia. In one particular disorder, a mitochondrial DNA (mtDNA) mutation is responsible for a type of human hereditary deafness that worsens over time and can lead to a profound hearing loss.

Now, a team of researchers from Yale School of Medical have showed that the genetic reduction of the enzyme AMP kinase (AMPK) can rescue hearing loss in a genetically engineered mouse model containing a mitochondrial dysfunction, which results in a similar premature deafness.    

“Mitochondrial dysfunction causes human diseases, with an estimated occurrence of 1 in 5,000 to 10,000 live births,” explained senior investigator Gerald Shadel, Ph.D., professor of pathology and genetics at the Yale School of Medicine. “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.”

The investigators bred transgenic mice that systemically overexpress the gene that encodes for the transcription factor B1, mitochondrial TFB1M (mtTFB1)—which modifies the 12S ribosomal RNA of mitochondrial ribosomes that are necessary to express mtDNA-encoded genes. The transgenic (Tg)-mtTFB1 mice developed hearing loss at a much more rapid rate than the wild-type controls.

The findings from this study were published recently in the American Journal of Pathology through an article entitled “Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness.”

To try and grasp the impact of the mitochondrial mutation in the engineered mice, the Yale researchers compared the anatomical and functional differences in the hearing pathways of the Tg-mtTFB1 mice vs. non-transgenic controls. The scientists 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,” noted lead author Sharen McKay, Ph.D., research associate in the department of pathology, Yale School of Medicine.

Specifically, the authors noted that the pathway to hearing loss in the Tg-mtTFB1 mice was initiated by mitochondrial reactive oxygen species that stimulate the enzyme AMPK, which in turn activated deleterious signaling events in specific parts of the inner ear. This lead the research team to surmise that the reductions of AMPK activity might prevent the hearing loss within the Tg-mtTFB1 mice.

To test their hypothesis, the researchers bred a strain of Tg-mtTFB1 mice in which they genetically knocked out one allele of the AMPK gene. What they observed was that the Tg-mtTFB1 mice displayed the expected increase in auditory brainstem response (ABR) threshold indicative of hearing loss between 9 and 12 months of age. However conversely, Tg-mtTFB1 mice in which the AMPK gene was also knocked-out had ABR thresholds indistinguishable from those of controls—indicating that AMPK mediates the pathway toward hearing loss in these mice and may be a possible druggable target.

“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.