Copper is a key element in the survival and normal development of humans but it is also toxic to cells when mishandled. In fact even mild disruption of copper homeostasis causes a wide array of disorders including diabetes, cardiovascular disease, Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. The requirement for copper is in part due to its role as a cofactor in the terminal electron transport chain complex cytochrome c oxidase. Though copper has an essential role in mitochondrial function, our knowledge of how it is recruited to, and distributed within, the organelle is very limited. The hypothesis to be tested here is that mitochondrial carrier family proteins that are used for translocation of substrates across the inner membrane are critical to copper homeostasis. The proposed aims and experiments combine in vivo and in vitro analysis of copper dependent phenotypes and transport assays to establish a role for a mitochondrial carrier family protein in copper transport. We will demonstrate the copper transport function of this protein in cell culture and an animal model by assessing the abundance and activity of copper-dependent enzymes, total copper in mitochondria and total copper in whole cells. Data generated from the experiments proposed in these aims will result in significant advances in our understanding of mitochondrial copper homeostasis in humans. The impact of this proposal is that knowledge gained by identifying a mitochondrial copper transporter can contribute to our understanding basic biology but also to a wide spectrum of diseases caused by copper mishandling or mitochondrial dysfunction. Many of these diseases are currently untreatable and this proposal will provide a potential druggable target for therapeutic intervention.
Mitochondrial respiratory chain defects account for the majority of fatal genetic diseases of metabolism. However, we cannot determine the cause of some of these disorders because we lack a complete understanding of the respiratory chain enzyme assembly process. One important step in respiratory chain assembly is the insertion of cofactors required for the function of these enzymes. In particular, the means by which copper, a cofactor required by the final enzyme complex in the respiratory chain, is imported into mitochondria is not known. This project aims to characterize the copper transport pathway in mitochondria that will serve as a potential target for diagnosis and therapy of copper related diseases.
| Boulet, Aren; Vest, Katherine E; Maynard, Margaret K et al. (2018) The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis. J Biol Chem 293:1887-1896 |
| Baker, Zakery N; Cobine, Paul A; Leary, Scot C (2017) The mitochondrion: a central architect of copper homeostasis. Metallomics 9:1501-1512 |
