Diseases caused by mitochondrial transport proteins

In agreement with their central role in metabolism and physiology, many dysfunctional mitochondrial transporters cause human disease. With the discovery of other transport proteins, it is likely that more will be implicated.

Figure Mutations of the mitochondrial aspartate/glutamate carrier citrin that lead to citrin deficiency.

Ten different human diseases have been associated with dysfunctional mitochondrial carriers [1][2]. For example, citrin deficiency is a metabolic disease caused by a defective mitochondrial aspartate/glutamate carrier, leading to impaired export of aspartate from the mitochondrion, which in turn is required for the urea cycle [3]. The carrier is a chimera of three domains. We have solved the structure of the regulatory domain of citrin and have demonstrated that it forms a homo-dimer via dimerization of the N-terminal domain [4]. The N-terminal domain contains eight EF-hands (rainbow), but only EF-hand 2 binds calcium (green spheres). The C-terminal domain (wheat) is bound in a conserved hydrophobic groove of the N-terminal domain. The regulatory domain contains six missense mutations (blue spheres), whereas the carrier domains (light blue), modelled on the yeast ADP/ATP carrier [5], contain twenty missense mutations (red spheres).

We will identify mitochondrial transport proteins that are involved in human disease and we will characterise mutations that lead to dysfunctional carriers in order to understand their impact on physiology.


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