Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Abstract/Contents
- Abstract
- Dynamin-related protein 1 (Drp1) is a large cytosolic GTPase that orchestrates mitochondrial fission, the process by which mitochondria divide. This process is important for a variety of cellular functions including removal of damaged mitochondria, and regulation of oxidative metabolism and apoptosis. A variety of signals can activate Drp1, stimulating its translocation to the mitochondria and oligomerization into a constricting loop. Drp1 binds to and is regulated by at least four mitochondrial adaptors, Fis1, Mff, MiD49, and MiD51. Binding to mitochondrial Fis1 is linked to the cellular stress response and seems to be dispensable for normal physiological function, since inhibitors are not toxic in many cell types and in vivo. In contrast, inhibiting Drp1 binding to Mff results in mitochondrial dysfunction. When cell stress is high, Fis1-mediated mitochondrial fission increases dramatically resulting in excessive fission and a fragmented mitochondrial network. These small spherical mitochondria have a lower mitochondrial membrane potential resulting in high ROS production, metabolic collapse, release of cytochrome c, and cell death. Consequently, Drp1 has been identified as an attractive drug target offering the potential to block cell stress in diseases such as neurodegeneration, cardiac ischemia, and sepsis. However, since Drp1-Mff interaction is needed for mitochondrial quality control, general inhibition of Drp1 function may lead to on-target toxicity. Inhibition of Drp1-Fis1 interaction without blocking Drp1-Mff function could offer a way of selectively inhibiting stress-induced mitochondrial fission while maintaining mitochondrial quality. P110, a peptide-inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis, without blocking physiological functions of Drp1. However, as a peptide, P110 has pharmacokinetic limitations. We therefore sought to better understand the molecular basis of P110's regulation of Drp1, and using this information, develop a small molecule that mimics P110's benefit. Ultimately, we hope to translate our findings into treatments for chronic diseases associated with excessive mitochondrial fission.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Rios, Luis Carl |
|---|---|
| Degree supervisor | Mochly-Rosen, Daria |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Chistol, Gheorghe |
| Thesis advisor | Ferrell, James Ellsworth |
| Degree committee member | Chistol, Gheorghe |
| Degree committee member | Ferrell, James Ellsworth |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Luis Carl Rios. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/kr276mv9026 |
Access conditions
- Copyright
- © 2022 by Luis Carl Rios
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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