Mitochondrial Copper in Mammals
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. 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. his work is done in collaboration with Scot Leary, Dept. of Biochemistry, University of Saskatchewan and is funded by the NIH.
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Major questions include:
1) What are the key residues for SLC25A3 to function as a copper transporter?
2) How does SLC25A3 discriminate between copper and phosphate?
3) Can the phenotypes of a heart specific knockout of slc25a3 be reversed by copper?
4) Role of other mitochondrial carrier family proteins in COX assembly?
Selected publications related to mammalian mitochondrial copper homeostasis
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Boulet A, Vest KE, Maynard MK, Gammon MG, Russell AC, Mathews AT, Cole SE, Zhu X, Phillips CB, Kwong JQ, Dodani SC, Leary SC, Cobine PA. The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis. J Biol Chem. 2018 Feb 9;293(6):1887-1896. PubMed PMID: 29237729; PubMed Central PMCID: PMC5808751.​
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Baker ZN, Jett K, Boulet A, Hossain A, Cobine PA, Kim BE, El Zawily AM, Lee L, Tibbits GF, Petris MJ, Leary SC. The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart. Hum Mol Genet. 2017 Dec 1;26(23):4617-4628. PubMed PMID: 28973536; PubMed Central PMCID: PMC5886179.
Hlynialuk CJ, Ling B, Baker ZN, Cobine PA, Yu LD, Boulet A, Wai T, Hossain A, El Zawily AM, McFie PJ, Stone SJ, Diaz F, Moraes CT, Viswanathan D, Petris MJ, Leary SC. The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis. Cell Rep. 2015 Feb 12;PubMed PMID: 25683716.​
Leary SC, Cobine PA, Kaufman BA, Guercin GH, Mattman A, Palaty J, Lockitch G, Winge DR, Rustin P, Horvath R, Shoubridge EA. The human cytochrome c oxidase assembly factors SCO1 and SCO2 have regulatory roles in the maintenance of cellular copper homeostasis. Cell Metab. 2007 Jan;5(1):9-20. PubMed PMID: 17189203.