Getting out what you put in: Copper in mitochondria and its impacts on human disease

Cobine, Paul A.; Moore, Stanley A.; Leary, Scot C.

doi:10.1016/j.bbamcr.2020.118867

Cited by 137 publications

(132 citation statements)

References 120 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…It is not surprising that MCF proteins are present across all eukaryotes given their fundamental roles in maintaining cellular physiology. We hypothesize that Cu transport to mitochondria was an important consideration in eukaryogenesis as it is required to maintain the activity of the electron transport chain and provide an advantage to the ancestral eukaryote ( Cobine et al, 2021 ). Conservation of this activity across diverse organisms may provide a phylogenetic signal with which to resolve residues that dictate PIC2 and MIR1 substrate specificities.…”

Section: Resultsmentioning

confidence: 99%

“…However, given the fatal disorders that result from too much or too little Cu or iron it is unlikely that their transport is left to chance (Xu, Barrientos, and Andrews 2013). Storage in the mitochondrial matrix may have evolved as a mechanism to ensure Cu availability for COX assembly in an early endosymbiont that was subsequently retained during eukaryogenesis (Cobine, Moore, and Leary 2020). Additional roles for Cu in the matrix remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with a mitochondrially restricted function for COX17 in Cu handling, yeast cells lacking this gene accumulate wild-type levels of Cu in mitochondria (Cobine et al 2004). In fact, attempts to isolate a protein that delivers Cu to mitochondria led to the identification of a nonproteinaceous ligand (CuL) that accumulates in the matrix (Cobine, Moore, and Leary 2020;Vest, Zhu, and Cobine 2019;Vest and Cobine 2011;Cobine et al 2006;Cobine et al 2004).…”

Section: Understanding Cu Transportmentioning

confidence: 96%

“…there is no experimental evidence for other metal ions being transported by PIC2. The transport of ionic Cu could be a mechanism to limit cytosolic accumulation of Cu during Cuoverload induced stress (Vest et al 2013;Cobine, Moore, and Leary 2020). Crosslinking and damage of mitochondrial membranes induced by Cu has been observed in models of Cuoverload, such as the Long-Evans Cinnamon rat (Zischka et al 2011).…”

Section: Understanding Cu Transportmentioning

confidence: 99%

See 3 more Smart Citations

Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes

Zhu

Boulet

Buckley

et al. 2021

eLife

View full text Add to dashboard Cite

The mitochondrial carrier family protein SLC25A3 transports both copper and phosphate in mammals yet in Saccharomyces cerevisiae the transport of these substrates is partitioned across two paralogs: PIC2 and MIR1. To understand the ancestral state of copper and phosphate transport in mitochondria, we explored the evolutionary relationships of PIC2 and MIR1 orthologs across the eukaryotic tree of life. Phylogenetic analyses revealed that PIC2-like and MIR1-like orthologs are present in all major eukaryotic supergroups, indicating an ancient gene duplication created these paralogs. To link this phylogenetic signal to protein function, we used structural modelling and site-directed mutagenesis to identify residues involved in copper and phosphate transport. Based on these analyses, we generated a L175A variant of mouse SLC25A3 that retains the ability to transport copper but not phosphate. This work highlights the utility of using an evolutionary framework to uncover amino acids involved in substrate recognition by mitochondrial carrier family proteins.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Understanding Cu Transportmentioning

confidence: 96%

Section: Understanding Cu Transportmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes

Zhu

Boulet

Buckley

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…A non-proteinaceous ligand, whose molecular identity remains unknown, has been proposed to transport cytosolic copper to the mitochondria (3), where it is stored in the matrix (11). This mitochondrial matrix pool of copper is the main source of copper ions that are delivered to CcO subunits in a particularly complex process requiring multiple metallochaperones and thiol reductases (3, 12, 13). Specifically, copper from the mitochondrial matrix is exported to the intermembrane space via a yet unidentified transporter, where it is inserted into the CcO subunits by metallochaperones Cox17, Sco1, and Cox11 that operate in a bucket-brigade manner (13).…”

Section: Introductionmentioning

confidence: 99%

A genome wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

Garza

Griffin

Zulkifli

et al. 2021

Preprint

View full text Add to dashboard Cite

Copper is essential for the activity and stability of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Loss-of-function mutations in genes required for copper transport to CcO result in fatal human disorders. Despite the fundamental importance of copper in mitochondrial and organismal physiology, systematic characterization of genes that regulate mitochondrial copper homeostasis is lacking. To identify genes required for mitochondrial copper homeostasis, we performed a genome-wide copper-sensitized screen using DNA barcoded yeast deletion library. Our screen recovered a number of genes known to be involved in cellular copper homeostasis while revealing genes previously not linked to mitochondrial copper biology. These newly identified genes include the subunits of the adaptor protein 3 complex (AP-3) and components of the cellular pH-sensing pathway- Rim20 and Rim21, both of which are known to affect vacuolar function. We find that AP-3 and the Rim mutants impact mitochondrial CcO function by maintaining vacuolar acidity. CcO activity of these mutants could be rescued by either restoring vacuolar pH or by supplementing growth media with additional copper. Consistent with these genetic data, pharmacological inhibition of the vacuolar proton pump leads to decreased mitochondrial copper content and a concomitant decrease in CcO abundance and activity. Taken together, our study uncovered a number of novel genetic regulators of mitochondrial copper homeostasis and provided a mechanism by which vacuolar pH impacts mitochondrial respiration through copper homeostasis.

show abstract

Structural Basis of Ion Transport in Copper‐Transporting P _IB ‐Type ATPases

Bågenholm,

Gourdon

2024

Encyclopedia of Inorganic and Bioinorganic Chemistry

View full text Add to dashboard Cite

Maintaining correct copper levels is vital for all cells, as copper is required for a large number of cellular processes, but is also toxic due to its high reactivity. Such regulation is accomplished using a range of processes, including the P IB‐1 ‐subgroup of P‐type ATPases. These primary active transporters exploit ATP to shuttle copper across cellular membranes, either out of the cell or into various organelles for cellular use, such as incorporation into copper‐dependent proteins. The pumping of copper across the membrane follows a conserved scheme, called the Post‐Albers cycle, where the protein cycles through a series of states, from inward‐open (E1) to inward‐occluded (E1P), outward‐open (E2P), and outward‐occluded (E2) and back, coupled to phosphorylation by ATP and dephosphorylation. This is established via a conserved core consisting of three soluble A‐, P‐, and N‐domains, and a transmembrane domain formed by eight membrane‐spanning helices, MA, MB, and M1–M6, as well as a varying number of metal‐binding domains MBDs, which typically are part of the N‐terminus. Copper is delivered to the P IB‐1 ‐transporter from small molecule or protein copper chaperones inside the cytoplasm, likely assisted by an MBD. The metal is then transferred to a methionine of M1 at the membrane interface, which relocates it to two conserved cysteines of the CPC motif in M4. Next, one or two high‐affinity‐binding sites are established in the M‐domain, again utilizing cysteines and methionines. Finally, release is achieved via an outward‐facing exit tunnel lined by methionines. While much of this pathway has been elucidated through determined molecular structures, important questions remain, for example, regarding the number of high‐affinity‐binding sites and the roles of the MBDs. Here, the structural details of the transport of copper through P IB‐1 ‐type ATPases will be described.

show abstract

Getting out what you put in: Copper in mitochondria and its impacts on human disease

Cited by 137 publications

References 120 publications

Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes

Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes

A genome wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

Structural Basis of Ion Transport in Copper‐Transporting P _IB ‐Type ATPases

Contact Info

Product

Resources

About

Getting out what you put in: Copper in mitochondria and its impacts on human disease

Cited by 137 publications

References 120 publications

Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes

Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes

A genome wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

Structural Basis of Ion Transport in Copper‐Transporting P IB ‐Type ATPases

Contact Info

Product

Resources

About

Structural Basis of Ion Transport in Copper‐Transporting P _IB ‐Type ATPases