Otic Capsule Lipidomics Profiling Reveals Insights into Hearing and the Response to Noise

Hearing loss is a major global health concern, estimated to affect more than 20% of the world’s population. Noise-induced hearing loss creates much of this burden; it is the number two cause overall of hearing loss and the leading cause in young adults. Worldwide, over 1 billion young adults are thought to be at risk of hearing loss – a highly concerning statistic given that NIHL often permanently damages the inner ear and has no treatment. As it is for other parts of the nervous system, metabolism is essential for normal inner ear function and the response to trauma. However, despite the fact that alterations in lipid metabolism have been associated with certain types of hearing loss, little is known about how noise exposure impacts lipid metabolism, and the roles of lipids in noise-induced hearing loss. The goal of my dissertation research was to begin to close these gaps in knowledge by: (1) developing techniques for reproducible lipidomics interrogations of otic capsules, (2) describing the lipidome of the inner ear during normal acoustic conditions and (3) the lipid changes that occur during acoustic over-exposure, and (4) performing preliminary investigations into the lipidome of deaf mice and the relationship between food deprivation and hearing. First, I address the challenges of, and provide solutions for, the reproducible preparation, extraction, and processing of otic capsules for lipidomics. Then, utilizing these methods, I identify noise-induced lipid changes in fatty acids (FAs) and acylcarnitines (CAR), and demonstrate that β-oxidation is a key noise-altered pathway. Using an inhibitor of carnitine palmitoyl transferase 1A (CPT-1A), Etomoxir, I show that NIHL can be prevented by reducing mitochondrial entry of long-chain FA, whereas this inhibition has no effect on hearing function under normal conditions. My results suggest that during noise exposure the hair cells of the organ of Corti consume FAs through β-oxidation, and that inhibition of this pathway significantly protects against noise-induced inner hair cell loss. Finally, my preliminary experiments into the lipidome of mice lacking hair cells (Pou4f3-DTR) suggest β-oxidation occurs in hair cells, while my preliminary experiments on the effect of food deprivation on hearing demonstrate the resilience of the inner ear to changes in circulating metabolites. The identification of β-oxidation as a potentially viable therapeutic target for the prevention of NIHL represents an important advancement in hearing research considering that there are no FDA-approved pharmacologic therapies for reducing noise-induced damage. Collectively, the tools developed in this research, and the insights gained, establish an exciting framework for otic capsule lipidomic interrogations, and the therapeutic potential of altering lipid metabolism to prevent NIHL.