The Role of Aco2 in progressive hearing loss - PROJECT SUMMARY/ABSTRACT Deafness is a significant health concern that affects more than 450 million people worldwide, and both environmental insults and genetic mutations are contributing factors. The auditory organ in the inner ear is composed of sensory hair cells that detect and transmit sound vibrations. Hair cells are innervated by bipolar spiral ganglion neurons (SGNs) that relay auditory signals from the hair cells to the brainstem. Damage causing SGN degeneration or affecting SGN projections or synapses with hair cells leads to hearing loss. Mitochondrial dysfunction is a common cause of pathologies targeting organs that require large amounts of energy to perform optimally, such as neurons. Nuclear DNA mutations in genes encoding mitochondrial proteins can affect mitochondrial biogenesis or energy metabolism pathway, affecting auditory function in either case. A focus of this study, variants in the mitochondrial ACO2 protein have been associated with optic nerve atrophy, seizures, and hearing loss in young children. ACO2 is a nuclear gene that produces aconitase hydratase 2, an early enzyme in the tricarboxylic acid cycle. Unfortunately, cellular or mechanistic insight into ACO2-related conditions is lacking in part due to the absence of adequate animal models. We identified a spontaneous recessive R56L amino acid substitution in the mouse Aco2 gene based on circling behavior. Homozygotes are viable but show early-onset progressive hearing loss at 1 month of age followed by severe SGN loss at 2 months. I propose that the ACO2 R56L protein variant results in SGN apoptosis due to mitochondrial dysfunction, explaining early-onset hearing loss. Aim 1 of this proposal will track SGN defects in the Aco2 R56L mutants from developmental stages to young adults. Aim 2 will investigate how the R56L mutation affects the dose and localization of the ACO2 protein, and establish how SGN mitochondria number and distribution is altered in time in mutants. Aim 3 will attempt to rescue mitochondrial defects and loss of SGNs in mutants via metabolic supplementation. This will first be tested in organ culture prior to exploiting these results in live mice to improve auditory function. The proposed research has the potential to help develop realistic treatments to prevent or rescue hearing loss in ACO2 patients. Moreover, the new Aco2 R56L mouse strain will be invaluable to model other neurological disorders in ACO2 patients, including optic atrophy.
