Molecular determinants of cardiolipin signalling in mitochondria

My research focusses on mitochondria, which are important components ('organelles') of our cells, and are responsible for maintaining the stability of our cells. Mitochondria have two membranes, separating them from the rest of the cell; an inner, folded membrane and an outer membrane. Important regulatory pathways occur within mitochondria that have critical roles in human health and disease. Some of these pathways are only beginning to be uncovered, including the one that I choose to focus on within this proposal. I aim to unlock the ways in which the hallmark lipid of mitochondria, cardiolipin, is used as a signal for the mitochondrial degradation ('mitophagy') pathway. We know that during this mitochondrial life/death process cardiolipin is moved from the MIM to the MOM. Once it is there it acts as a signal for the cell to degrade the mitochondrion. We do not yet know how this process is physically able to occur, but new research implicates the protein NME4 in directly transferring cardiolipin across the two membranes. My work combining computer simulations of these molecules with experimental work will provide the first molecular level information on this pathway.

This programme will represent the first comprehensive, multidisciplinary molecular level study of both membranes of the mitochondria and how they behave in concert and give us new understanding of how we might control these pathways. This has important consequences in human health and disease, as the misregulation of these processes has been linked to neurodegenerative disorders, cardiomyopathy and neurological disease. There are also links between cancer drug resistance and these mitochondrial quality control pathways.

The new understanding generated by my research programme will be applied to study other related pathways and, long-term, will be expected to lead to potential new drug targets in mitochondrial quality control pathways. Advancements in understanding membrane protein-lipid interactions in general will also have implications for the advancement of drug discovery programmes. To maximise the exchange of knowledge and drive research forward in the field, my lab will link up with industrial partners throughout the course of the research programme.

The grand challenge of this research proposal is to use a concerted, multidisciplinary approach to characterise interactions within mitochondrial membranes in order to provide new insights into health-and disease-relevant quality control pathways.

To achieve this, the following impact objectives will be met:
1. Publish novel findings on the mitophagy pathway
2. Open and transparent shared resource for my work on mitochondrial membranes
3. Exhaust opportunities for long-term human health impact by identifying new pathways in mitochondrial quality control

By meeting these objectives, this research will provide benefits to the following groups:

1) Stakeholders
a. my work will be beneficial to industrial partners, interested in the mitophagy pathway as a target. My findings on the NME4 CL pathway with have direct and immediate impact in the short term (1-2 years)
b. I am in contact with pharmaceutical companies to incorporate my mitochondrial models into their platforms (2 year onwards)
2) Health care and policy:
a. My research has longer term impact in human health, by fully characterizing a newly described lipid signalling pathway, and how it connects to other mitochodnrial proteins involved in quality control.
3) Public
a. General public - science fairs
b. Schools - placements and talks
4) Academia: described fully in Beneficiaries Summary section.

The proposed research will provide major discoveries within the field of mitochondrial membrane transport and signalling. This is an ambitious research project which in the short term will allow progress in the field of understanding protein-lipid interactions, a rapidly expanding field. Over the course of the 4+3 years I expect to contribute not only to the field of mitochondrial control but also in driving forward method development, particularly in combining molecular simulation and experimental techniques in which I am uniquely qualified.

Aside from pure science knowledge, there Is a clear pathway to long term translational impact in understanding the molecular basis of mitophagy and mitochondrial quality control which has important implications in ageing and neurodegenerative disorders. I will maintain close links to industry where appropriate in order to realise any potentially medically relevant findings and maximise the impact of the underlying research. Understanding the molecular basis of lipid interactions on the function and properties of their partner/'host' proteins will allow a broader understanding of the roles the membrane environment plays on membrane protein function.

In terms of the long term impact (extending beyond the duration of this Future Leaders Fellowship), further mitochondrial signalling pathways will be chosen based on those having measurable impact in human health and diseases, and industrial partners that may be interested in specific parts of this project will be identified. The commercial potential of any outcomes (eg by development of small molecules based on the findings of these calculations) will be maximized by protecting any Intellectual Property and targeting smaller biotech companies using the resources available at the Imperial College London innovation and translational research offices.

Where possible I have published in open access journals and will make every effort to disseminate the research outcomes from this proposal widely, by publishing high-impact open access publications, presentation at international research meetings, by maintaining and developing network of collaborators, and deposition of data into public domain. This includes making available my mitochondrial membrane simulation framework to the general simulation community, as well as linking it to established membrane protein databases (Orientations of Membrane Proteins and MemProtMD). Furthermore,research outcomes will be disseminated to the general public via press releases eg on the Imperial College London website.