The role of mitochondrial transporters in human physiology and adverse drug effects

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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.