Copper Import into the Mitochondrial Matrix in Saccharomyces cerevisiae Is Mediated by Pic2, a Mitochondrial Carrier Family Protein

Vest, Katherine E.; Leary, Scot C.; Winge, Dennis R.; Cobine, Paul A.

doi:10.1074/jbc.m113.470674

Cited by 96 publications

(119 citation statements)

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“…4B). These data suggest that SLC25A3 can function as a copper transporter, particularly because pic2⌬ yeast do not exhibit any phosphate defects and increased phosphate levels do not suppress the copper defects in this mutant (18).…”

Section: Heterologous Expression Of Slc25a3 In Yeast and Lactococcus mentioning

confidence: 84%

“…As an additional assessment of copper transport, we used silver in place of copper as silver is more toxic to L. lactis and is widely used to demonstrate copper transport. In this assay, expression of a functional copper transporter increases the silver sensitivity of L. lactis (18,31). Silver was more toxic to L. lactis expressing human SLC25A3-A when compared with L. lactis harboring an empty expression vector, as indicated by a lack of growth at 24 h in silver-containing medium (Fig.…”

Section: Heterologous Expression Of Slc25a3 In Yeast and Lactococcus mentioning

confidence: 92%

“…The MCF protein Pic2 is a mitochondrial copper transporter in budding yeast (18). To test for the copper transport function of SLC25A3 in yeast, we expressed the human SLC25A3-A cDNA under the control of the constitutive ADH1 promoter in a pic2⌬ background.…”

Section: Heterologous Expression Of Slc25a3 In Yeast and Lactococcus mentioning

confidence: 99%

“…Cultures were grown in 1% yeast extract, 2% peptone with 1% glucose medium at 30°C for 24 -36 h. Preparation and fractionation of mitochondria were performed as described previously (17). The mitochondrial copper uptake rate was obtained by incubation of isolated mitochondria with copper for 0 -4 min at room temperature, centrifugation, and then acid digestion followed by ICP-OES (PerkinElmer Life Sciences 7300-DV) as described previously (18).…”

Section: Yeast Strainsmentioning

confidence: 99%

“…In yeast, biochemical depletion of the matrix copper pool results in a COX defect, suggesting that this pool is redistributed to the IMS for maturation of the holoenzyme (5). The mitochondrial carrier family (MCF) protein Pic2 acts as an importer of copper into the matrix (18). The human genome encodes for more than 50 MCF proteins that are involved in translocation of substrates across the IM, including various TCA intermediates and nucleoside di-and triphosphates for energy metabolism (19).…”

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confidence: 99%

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The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Boulet

Vest

Maynard

et al. 2018

Journal of Biological Chemistry

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108

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Edited by Ruma BanerjeeCopper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.Mitochondrial dysfunction contributes to the pathogenesis of heart failure, neurodegenerative disorders, myopathies, and diabetes (1). Mitochondria are dynamic, double membranebound organelles with a semi-permeable outer membrane that allows exchange of metabolites between the cytosol and the intermembrane space (IMS).5 In contrast, the inner membrane (IM) that separates the IMS and the matrix is tightly sealed. Thus, numerous transporters are required to provide the matrix with a diverse range of substrates that are necessary to support metabolism, the biogenesis of iron-sulfur clusters, and the assembly of the electron transport chain (ETC) required for oxidative phosphorylation (2).Cytochrome c oxidase (COX) is the terminal electron-accepting complex of the ETC. Mammalian COX contains 14 major subunits, two of which bind three redox centers required for electron transfer (3). The catalytic core consists of the mitochondrially-encoded subunits COX1, COX2, and COX3. COX2 binds the binuclear Cu A site required for accepting electrons from cytochrome c. These electrons are then transferred to the cofactors of COX1, first to heme a and then to the heme a 3 -Cu B site where oxygen is bound. COX biogenesis requires Ͼ25 accessory proteins known as COX assembly factors (1). The overwhelming majority of ETC defects that underlie mitochondrial dysfunction and human disease is caused by pathogenic mutations in accessory factors (1). At least nine of these factors facilitate the insertion of the copper cofactors that are essential for the catalytic competence of the COX holoenzyme (4). In yeast, it has been demonstrated that the copper used for COX assembly comes from the matrix, and this matrix copper pool is conserved in mammals (5, 6). Howe...

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Section: Heterologous Expression Of Slc25a3 In Yeast and Lactococcus mentioning

confidence: 84%

Section: Heterologous Expression Of Slc25a3 In Yeast and Lactococcus mentioning

confidence: 92%

Section: Heterologous Expression Of Slc25a3 In Yeast and Lactococcus mentioning

confidence: 99%

Section: Yeast Strainsmentioning

confidence: 99%

mentioning

confidence: 99%

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The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Boulet

Vest

Maynard

et al. 2018

Journal of Biological Chemistry

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108

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Metal Homeostasis in Plant Mitochondria

Vigani

Hanikenne

2017

Annual Plant Reviews, Volume 50

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Metal Homeostasis in Plant Mitochondria

Vigani

Hanikenne

2018

Annual Plant Reviews Online

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This chapter discusses the current knowledge concerning the mitochondrial metal homeostasis in plants. The most important metals present in plant mitochondria are iron (Fe), zinc (Zn), copper (Cu), manganese (Mn), molybdenum (Mo) and cobalt (Co), which constitute the mitochondrial metallome. In mitochondria, Fe plays its biological function essentially as an enzyme co‐factor and it is mainly bound to ligands, such as Fe‐heme groups and Fe‐sulfur (Fe‐S) clusters, which are components of the mitochondrial respiratory complexes. The loss of Cu suggests damage to soluble mitochondrial cuproproteins and the membrane‐bound electron transport chain, whereas the loss of Fe and Mn suggests that H 2 O 2 treatment damaged the matrix metalloproteins such as Fe‐S‐containing aconitase and Mn‐containing superoxide dismutase (MnSOD). The decrease in the membrane‐bound Cu may be linked to the decrease of Complex IV (COX) complexes, which are the major Cu user in mitochondria.

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Copper Import into the Mitochondrial Matrix in Saccharomyces cerevisiae Is Mediated by Pic2, a Mitochondrial Carrier Family Protein

Cited by 96 publications

References 37 publications

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

Metal Homeostasis in Plant Mitochondria

Metal Homeostasis in Plant Mitochondria

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