The role of mitochondrial transporters in human physiology and adverse drug effects(On the University’s application portal, please select "PhD in Biological Science at the MRC Mitochondrial Biology Unit").
The inner membrane of mitochondria is impermeable for most large and polar molecules and thus a large number of transporters is required to link the biochemical pathways of the cytosol with those of the mitochondrial matrix. Based on the known biochemical pathways that involve mitochondria, it is estimated that about 90 different transport steps must be present in mitochondria, but for 70% of them the transport protein has not been identified.
The first aim of this project is to identify the transport proteins involved in the transport of these key metabolites, nucleotides, and cofactors by using a combination different techniques. The second aim of this proposal is to study the effect of drugs and other compounds on the function of transport proteins to see whether they play a role in mitochondrial toxicity. The large number of serious disease phenotypes that occur when transport proteins are dysfunctional has demonstrated their importance in mitochondrial function and related physiology. It is possible that chemicals and drugs may directly interfere with substrate transport needed for normal mitochondrial function, leading to cellular and organ dysfunction similar to that seen in transporter-linked diseases. The third aim of the project is to study whether mitochondrial transport proteins are directly involved in the accumulation of drugs. Some chemicals and drugs pass through the mitochondrial membrane by diffusion, but others are likely to be actively transported and potentially concentrated in the mitochondria by the endogenous transport machinery. To identify possible mechanisms of active chemical/drug transport into mitochondria we will test the effect drugs have on the transport of compounds into mitochondria.
This is an Industrial CASE Award Studentship with co-supervision from the MRC Mitochondrial Biology Unit, Cambridge University and an industrial partner (GSK). The project will make use of expertise within both the MBU and GSK’s Mechanistic Safety and Disposition Department to develop fundamental understanding of mitochondrial transport mechanisms and their importance in disease and drug toxicity.
The student will spend a minimum of 3 months working at the premises of GSK during their 4-year project, giving them the opportunity to experience both an excellent academic laboratory and an industrial research environment during their studies.
Start date: January 2018
GlaxoSmithKline (GSK) is a large pharmaceutical company providing pharmaceuticals, vaccines, and consumer health products to millions of people around the world; helping people to do more, feel better and live longer.