Ren, Ziyu;
(2024)
Dynamic proteomics reveals the mitochondrial
permeability transition pore can be formed by multiple
proteins.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Background: Mitochondrial permeability transition (mPT) is a sudden increase in conductance across mitochondrial membrane (MM). The process is thought to be facilitated by the opening of a physical mega channel known as the mitochondrial permeability transition pore (mPTP). Irreversible opening of the mPTP leads to bioenergetic collapse and cell death which is thought to contribute heavily to ischemia-reperfusion (IR) injury following myocardial infarction. There have been repeated efforts to develop mPTP inhibiting drugs to treat IR injury, but clinical success has yet to be achieved. A major roadblock in the process of developing clinically relevant mPTP inhibitors is the yet unknown molecular identity of the mPTP. There are many suggested candidates for the mPTP where experimental evidence showed that they can modulate the mPTP. However, genetic ablation of any of these candidates failed to abolish mPTP activity, leading to the problem remaining unresolved. / Aims: This project aimed to find the channel forming component of the mPTP. CypD is the only undisputed regulatory component of the mPTP. I hypothesised that I could find the mPTP channel by screening for protein interactors of CypD. Although such screens have been done before, I carried out a dynamic screen where I induced mPTP opening via Ca2+ and compared the CypD interactome with/out mPTP opening. This was only possible with recently developed proteomics techniques and have never been caried out for CypD and the mPTP. / Results: The project returned the ATP Synthase, ANT, PiC, VDAC, HSPE1 as relevant CypD interactor hits. I also observed that CypD displayed increased interaction with the ATP Synthase, ANT, PiC and VDAC following mPTP induction via Ca2+ treatment, this increase is abolished when CsA is added. Additionally, I observed that HSPE1 showed increased interaction with CypD following mPTP induction when CsA is added or when CypD is desensitized to CsA. This suggest HSPE1 might be involved in a CypD regulated mPTP pathway that is insensitive to CsA. / Conclusions: The data here would suggest that multiple proteins can form the mPTP channel. I showed that the ATP Synthase, ANT and PiC displayed increased interaction with CypD following mPTP induction, and this interaction was eliminated in the presence of CsA. Although I did not show the process how these proteins form the mPTP, their ability to form the mPTP have been shown by previous work in the field. My work provides evidence that CypD interacts with multiple mPTP candidate proteins following Ca2+ induced mPTP which provides support for the multiple protein hypothesis of the mPTP. This would also explain why genetic deletion of any single mPTP candidate failed to abolish mPTP activity. Additionally, this work suggests the possible existence of a previously unknown CsA insensitive CypD mediated mPTP pathway which HSPE1 might be involved in.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Dynamic proteomics reveals the mitochondrial permeability transition pore can be formed by multiple proteins |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10185295 |
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