Staying alive: how do trypanosome parasite mitochondria deal with stress?

Mitochondria are called the powerhouse of the cell because they produce energy necessary for most eukaryotic cells to survive. They are hubs of other vital cellular processes, for example metabolic and programmed cell death pathways, guarding over that critical balance between the life and death of a cell. Faulty or stressed mitochondria can have massive implications for the health of eukaryotes. Indeed, mitochondrial dysfunction is now recognised as having a central role in both ageing and ageing-related diseases like neurodegenerative and cardiovascular disorders, which are major causes of morbidity and mortality worldwide.

For mitochondria to keep functioning, and the cell to stay alive, there are many complicated events that need to occur in a tightly regulated fashion. The majority of mitochondrial proteins are nuclearly-encoded and have to be synthesised in the cytosol. They are then imported into the organelle, targeted to specific compartments or membranes, and often then assembled into defined multiprotein complexes before they can function correctly. To stop faulty or stressed mitochondria affecting the health of the cell, overlapping mitochondrial quality control (MQC) pathways have evolved. A comprehensive understanding of the myriad of MQC mechanisms found in nature is required to potentially find therapies for debilitating chronic ageing-related diseases.

Remarkably, despite mitochondria being central to so much other cellular biology, our understanding of these organelles has come from only a small number of common model organisms. Recent investigations into understudied organisms however have repeatedly challenged these textbook paradigms, revealing that there is so much more divergence in fundamental mitochondrial functions than first thought. Additionally, plugging this huge gap in knowledge could lead to valuable new drug targets in disease-causing eukaryotes.

We study the mitochondrial biology of the trypanosome parasite. Trypanosomes are major pathogens of both humans and cattle in sub-Saharan Africa, threatening an estimated 60 million people and their livestock. The single mitochondrion of Trypanosoma brucei has yielded so many surprising examples of extraordinary biology that have redefined our vision of this organelle. We recently discovered two MQC pathways providing tolerance to mitochondrial stress in T. brucei (Dewar et al., Nat. Comms. 2022, Gerber et al., Life Sci. Alliance, 2023). These pathways were the first such pathways found in a non-classical model system, and have highly unusual features which we now need to dissect in molecular detail.

In this project, we will use state-of-the-art methods for genetic manipulation, including CRISPR/Cas9, and proteomics to shed light on an unusual MQC pathway in these divergent and medically important parasites. You will gain a diversity of valuable transferable skills in cell culture, molecular biology, biochemistry, microscopy, data analysis, scientific writing and oral presentation. We are based in the Division of Biomedical and Life Sciences at Lancaster University, a Top 3 UK Biomedical Sciences department, which is a stimulating and diverse community with an excellence in cell biology research.

Applicants should hold a minimum upper second-class honours degree in Biology or related discipline. A Masters degree is desirable.

For informal discussions and queries in advance of applying, please contact Dr Caroline Dewar; c.dewar1@lancaster.ac.uk

To apply, please send your CV (max 2 pages) including the names of two referees and cover letter (outlining your interest in this PhD and qualifications) to Dr Caroline Dewar; c.dewar1@lancaster.ac.uk