There are at least a dozen forms of mitochondrial-related deafness (both non-syndromic and syndromic forms, as well as aminoglycoside-induced) and associated vestibular disorders. After connexin-related deafness, mitochondrial-related deafness is the second most common form, responsible for 5% of all post-lingual deafness. Just one form of mitochondrial-related deafness (the A1555G mutation) is present in over half of all cochlear implant patients who become deaf due to aminoglycosides. Yet, most mitochondrial diseases are considered "rare" or "orphan" diseases, and have been largely ignored by the scientific community. Mitochondrial forms of deafness, however, are as common as several well-known neurological diseases, e.g., Hunting- ton's, ALS, or certain forms of muscular dystrophy. In other organs in the body, the structure of mitochondria and their role in apoptosis and cell death is a topic of intense research interest. Such a framework of structural studies is missing in the inner ear. This proposal aims to fill the gap by studying hair cell mitochondria in both whole animal and isolated mitochondrial prepara- tions for the purpose of addressing hair cell damage and cell death in mitochondrial-associated forms of deafness. Besides the emphasis on mitochondrial-related deafness, we think that this proposal merits consideration as an R21 proposal because we will be using imaging approach- es relatively new to the inner ear field to study mitochondrial fine structure in inner ear cells. We will also relate these findings to isolated sub-populations of inner ear mitochondria that we pre- dict will respond differently to ototoxic insults such as aminoglycoside or cisplatin exposure. With information gained from this proposal, therapeutics can be more precisely targeted toward specific parts of the mitochondrial respiratory chain that are compromised in ailing hair cells and can thus "rescue" those that have been exposed to environmental assaults (noise, chemothera- py, ototoxic antibiotics) or aging.
In other organs in the body, the structure of mitochondria and their role in apoptosis and cell death is a topic of intense research interest. Such a framework of structural studies is missing in the inner ear. This proposal aims to fill the gap by studying hair cell mitochondria for the ultimate purpose of addressing hair cell damage and death in mitochondrial-associated forms of deafness (syndromic, non-syndromic, antibiotic-induced, and chemotherapy-induced). Our laboratory is one of the few inner ear labs with experience in electron microscope tomography, thus we are well positioned to ask and answer detailed questions about mitochondrial structure and how it relates to inner ear function, specifically as regards mitochondrial responses to ototoxic agents.
|MartÃn-Sierra, Carmen; Requena, Teresa; Frejo, Lidia et al. (2016) A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease. Hum Mol Genet 25:3407-3415|
|Requena, Teresa; Cabrera, Sonia; MartÃn-Sierra, Carmen et al. (2015) Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease. Hum Mol Genet 24:1119-26|