Defects in mitochondrial biogenesis lead to a broad range of diseases including neurodegeneration, stroke, myocardial infarction, ischemia, and cancer; however, therapies to correct such diseases are not readily available. We propose to conduct a high throughput screen in the Molecular Libraries Production Center Network (MLPCN) identical to the one that, on a smaller screening scale, has already successfully identified inhibitors of a mitochondrial redox pathway for the import and assembly of proteins in the mitochondrial intermembrane space. Specifically, we will employ a straightforward in vitro enzymatic assay with recombinant Erv1, a sulfhydryl oxidase that functions in this pathway. We have developed a robust fluorescence assay to monitor Erv1 activity.
The aims of this proposal are to (1) identify small molecules that alter Erv1 function and then develop analogs for structure activity relationship (SAR) studies to identify specific chemical compounds that modulate Erv1 and (2) utilize these tools in secondary assays and develop probes that we can use in vertebrate systems to probe mitochondrial function, including the link to apoptosis. These studies will result in validated chemical probes for mechanistic studies of mitochondrial import and for potentially inducing/abrogating apoptosis. Given our success, we are confident that many novel compounds will be identified that are pertinent for understanding mitochondrial assembly in vertebrates. The medical importance of events regulated by mitochondrial assembly, such as apoptosis, indicates that the chemical genetic approach may also lead to the identification and development of novel therapeutic agents for diseases affected by dysfunctional mitochondria. Identification of these novel compounds, tied with our expertise in finding targets and our ability to exploit them to more fully understand mechanism, justifies our request to expand this screen through the MLPCN. This study is relevant to public health because it may lead to the development of new therapeutics for degenerative muscular and neural diseases.
This project will develop small molecules as probes to investigate the cause of neurodegenerative and degenerative muscular diseases that are initiated by defects in mitochondrial function. The mitochondrion generates energy for the cell and is linked to a broad range of diseases. Long-term, this project may lead to the development of therapeutics that modulate mitochondrial function in these diseases. ? ? ?
| Wang, Geng; Shimada, Eriko; Nili, Mahta et al. (2015) Mitochondria-targeted RNA import. Methods Mol Biol 1264:107-16 |
| Dabir, Deepa V; Hasson, Samuel A; Setoguchi, Kiyoko et al. (2013) A small molecule inhibitor of redox-regulated protein translocation into mitochondria. Dev Cell 25:81-92 |
