Section Copper (Cu) is an essential micronutrient that acts as a catalytic cofactor for a number of enzymes including cytochrome c oxidase (CcO), a critical enzyme required for mitochondrial energy production. Cu delivery to CcO is a complex process requiring multiple proteins, and loss-of-function mutations in several of the genes encoding these proteins cause fatal infantile disorders. Currently, no effective therapy exists for these fatal disorders. This is due, in part, to our incomplete understanding of how Cu is trafficked to the mitochondria and is delivered to the Cu-containing subunits of CcO. To address this gap in our knowledge, we use complementary approaches involving yeast genetics and biochemistry to discover and characterize the novel mitochondrial proteins that facilitate Cu delivery to CcO. Using these approaches, we have found the evolutionarily conserved mitochondrial proteins Coa4 and Coa6 as new members of the mitochondrial Cu delivery pathways to CcO. Now, we aim to define the biochemical functions of Coa4 and Coa6 in the Cu delivery process. Our preliminary findings, including the structure of human COA6, have led us to hypothesize that Coa4 and Coa6 play redox roles in Cu delivery to CcO. We will test this hypothesis by determining the in vitro and in vivo redox states of Coa4- and Coa6- interacting proteins and by defining the physical basis of interaction through genetic and protein:protein interaction studies. Thus, the proposed project addresses fundamental questions in Cu delivery mechanisms to CcO.
Section Inherited loss-of-function mutations in genes required for copper delivery to the respiratory enzyme cytochrome c oxidase disrupt mitochondrial energy metabolism and result in fatal infantile disorders. Using yeast genetics, we have identified novel genes that facilitate copper trafficking to cytochrome c oxidase. Now we will use biochemical approaches to define the functions of these newly identified genes to understand the process by which copper is delivered to the mitochondrial cytochrome c oxidase.
|Soma, Shivatheja; Latimer, Andrew J; Chun, Haarin et al. (2018) Elesclomol restores mitochondrial function in genetic models of copper deficiency. Proc Natl Acad Sci U S A 115:8161-8166|
|Basu Ball, Writoban; Baker, Charli D; Neff, John K et al. (2018) Ethanolamine ameliorates mitochondrial dysfunction in cardiolipin-deficient yeast cells. J Biol Chem 293:10870-10883|
|Basu Ball, Writoban; Neff, John K; Gohil, Vishal M (2018) The role of nonbilayer phospholipids in mitochondrial structure and function. FEBS Lett 592:1273-1290|
|Ghosh, Alok; Pratt, Anthony T; Soma, Shivatheja et al. (2016) Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2 biogenesis. Hum Mol Genet 25:660-71|
|Baker, Charli D; Basu Ball, Writoban; Pryce, Erin N et al. (2016) Specific requirements of nonbilayer phospholipids in mitochondrial respiratory chain function and formation. Mol Biol Cell 27:2161-71|
|Tomar, Dhanendra; Dong, Zhiwei; Shanmughapriya, Santhanam et al. (2016) MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. Cell Rep 15:1673-85|
|Jayasundara, Nishad; Kozal, Jordan S; Arnold, Mariah C et al. (2015) High-Throughput Tissue Bioenergetics Analysis Reveals Identical Metabolic Allometric Scaling for Teleost Hearts and Whole Organisms. PLoS One 10:e0137710|