Targeting DRP1-FIS1 interaction to prevent mitochondrial fragmentation and dysfunction in diseases
Abstract/Contents
- Abstract
- Mitochondria are dynamic organelles; they undergo fission and fusion as a part of normal physiology. Fusion allows mitochondria to replenish exhausted components and maintain the network whereas fission allows mitochondria to increase their number and shed damaged components. In healthy conditions, these opposing processes counteract each other to maintain mitochondrial size, shape and function. These processes are driven by large GTPases. Optic atrophy gene 1 (OPA1) is situated in the mitochondrial inner membrane and mediates inner membrane fusion and a pair of large GTPases, Mitofusin 1 and 2 (Mfn 1/2), are linked to the mitochondrial outer membrane and complete outer membrane fusion. However, mitochondrial fission is driven by a cytosolic GTPase, Dynamin related protein-1 (Drp1), which is localized to mitochondria through interactions with mitochondrial adapter proteins. Under basal conditions, Drp1 is recruited to outer mitochondrial membrane by Mitochondrial fission factor (Mff) and mitochondria undergoes physiological fission. However, during cell stress and diseases, Mitochondrial fission 1 protein (Fis1) recruits Drp1 to mitochondria which causes excessive mitochondrial fragmentation and dysfunction. This pathological fission results in fragmentation of mitochondrial network, elevated mitochondrial ROS, reduced membrane potential and ATP production. Mitochondrial fragmentation and dysfunction is a driver of oxidative stress, metabolic imbalance and inflammation and is associated with neurodegenerative diseases, cardiovascular diseases and inflammatory diseases. Regardless of the etiology, mitochondrial fragmentation and dysfunction is known to contribute to the pathogenesis of these diseases. Studies with a bioactive peptide, P110, that disrupts Drp1-Fis1 interaction have been shown to curb mitochondrial fragmentation and dysfunction in cell models and delay disease progression and increase survival in preclinical animal models. However, peptides have pharmacokinetic liabilities and are subject to rapid metabolic degradation making them unsuitable for development as therapeutics. Therefore, I set out to identify new small molecules that can inhibit Drp1-Fis1 interaction. Using molecular modeling, structural elucidation and high throughput assay development, I identified small molecules that engage with Drp1 and Fis1 and disrupt their ability to cause mitochondrial pathology. I am going to discuss this work in Chapters 1-4 of this thesis. The world was battling with COVID-19 pandemic during the first half of my PhD, and along with my primary thesis work on mitochondria, I also contributed to further the understanding of druggable components of SARS-CoV-2 and identifying agents that can inhibit infection. I worked on understanding how mutations on spike protein allows SARS-CoV-2 to become more infectious and transmit between animal species. I also identified conserved sites within SARS-CoV-2 spike protein that can be targeted with small molecules or therapeutic antibodies. I also worked to elucidate the structural basis of inhibition of a critical protease, PLpro, from SARS-CoV-2 by a potent and selective covalent inhibitor and I am currently working on its optimization. Publications that resulted from these work are mentioned in the appendix section of this thesis.
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 | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Pokhrel, Suman |
|---|---|
| Degree supervisor | Mochly-Rosen, Daria |
| Degree supervisor | Wakatsuki, Soichi |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Wakatsuki, Soichi |
| Thesis advisor | Grimes, Kevin |
| Thesis advisor | Rogala, Kacper |
| Degree committee member | Grimes, Kevin |
| Degree committee member | Rogala, Kacper |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Suman Pokhrel. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/qm524tw1241 |
Access conditions
- Copyright
- © 2023 by Suman Pokhrel
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...