Key enzyme activity in inherited deafness

Genetics

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Researchers from Yale School of Medical, Connecticut, USA have showed that the genetic reduction of the AMP kinase (AMPK) enzyme can rescue hearing loss in genetically engineered mice with mitochondrial dysfunction causing deafness.

Human mitochondrial DNA mutations are responsible for a wide range of disorders, from metabolic conditions, to cardiac dysfunction, and even blindness. An extreme example of a tissue-specific mitochondrial anomaly, an A1555G mutation in the 12S rRNA gene, results in maternally inherited, non-syndromic deafness.

The research team from Yale studied transgenic mice that systemically overexpress a gene that codes for the transcription factor B1, mitochondrial TFB1M (mtTFB1). They proposed that this model mirrors some aspects of A1555G-related disease. They compared transgenic mice with normal controls in order to understand the role of the mitochondrial mutation. Their findings included reduced endocochlear potential, indicating significant stria vascularis dysfunction, decreased auditory brainstem response and prolonged wave I latency, consistent with apoptosis of spiral ganglion neurons.

The results were interpreted to mean that the pathway to hearing loss in the transgenic mice was initiated by mitochondrial reactive oxygen species (ROS) that stimulate the AMPK enzyme, causing damage to specific parts of the inner ear. Their conclusion was that reductions in AMPK activity might prevent this type of hearing loss. This points to a possible research pathway in humans based on inhibiting AMPK.

Source: Genetic engineering and biotech news; McKay SE, et al. Auditory Pathology in a Transgenic mtTFB1 Mouse Model of Mitochondrial Deafness. The American Journal of Pathology 2015 Oct 27.

C.S.