Synthetic biodetector of subcellular mitothermogenesis in NIHL model system.
Abstract
We propose to develop a synthetic biodetector to investigate mitochondrial thermogenesis (mitothermogenesis) in a noise-induced hearing loss (NIHL) cellular model. Changes in mitochondrial activity have been shown to affect its thermal output. We speculate that such effect is a critical component in the regulation of pathways associated with NIHL. This proposal will address the thermal dependence of mitochondria to regulate metabolic and signaling pathways central to NIHL.Oxidative stress drives NIHL through the activation of multiple cellular pathways leading to hair cell death in the organ of Corti. Subcellular factors mediated by mitochondrial function regulate the threshold response of NIHL-dependent oxidative stress pathways to influence an individual s susceptibility to noi"se.In our previous ONR funded project, we showed that NIR at 810 nm prevented inflammation and oxidative stress in cochlear cells"" HEI-OC1 under ototoxic challenges (Bartos et al, 2016). Although data indicate that mitochondria are central to the NIR response, t""he role of intracellular heat transfer has not been addressed due to lack of resolution of previously available tools.Recently, cu""stom-designed intracellular fluorescent probes have revealed inhomogeneous heat distribution within cells where thermal hot spots, p""ossibly colocalized with organelles, were found within cooler subcellular regions. Mitochondria temperature could vary from 6-9~C in"" the mitochondria and reach temperatures up to 50~C (Nakano et al, 2017; Chretien et al, 2017), a 13~C temperature differential in t"he cells.We expect that thermal inhomogeneity to significantly impact the regulation of a large array of cellular functions. In th"e context of NIHL, critical functions such as energy homeostasis, control of oxidative stress response and early regulation of apopt""osis may be under the dependence of mitochondrial thermal activity. We envision the possibility to thermally regulate mitochondria,"" perhaps using NIR photons, and maintain them in a state most protective for cochlear cells.We hypothesize a thermal dependence of"" mitochondrial activity, within cochlear mechanosensory cells, that regulate key drivers of NIHL susceptibility. We term this mechan"ism mitothermogenesis. Fundamental and critically important questions to be addressed include identification of the dynamic range of" operational temperatures mitochondria utilize under normoxic, hypoxic and oxidative stress microenvironments. In the context of hea""ring loss, mitothermogenesis is likely driven by an external factors impacting oxidative stress.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 29, 2017
- Source ID
- N000141712822
Entities
People
- Yohann Grondin
Organizations
- Office of Naval Research
- President and Fellows of Harvard College
- United States Navy