PMID- 26669719
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20201209
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 25
IP  - 4
DP  - 2016 Feb 15
TI  - Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2 
      biogenesis.
PG  - 660-71
LID - 10.1093/hmg/ddv503 [doi]
AB  - Biogenesis of cytochrome c oxidase (CcO), the terminal enzyme of the 
      mitochondrial respiratory chain, is a complex process facilitated by several 
      assembly factors. Pathogenic mutations were recently reported in one such 
      assembly factor, COA6, and our previous work linked Coa6 function to 
      mitochondrial copper metabolism and expression of Cox2, a copper-containing 
      subunit of CcO. However, the precise role of Coa6 in Cox2 biogenesis remained 
      unknown. Here we show that yeast Coa6 is an orthologue of human COA6, and like 
      Cox2, is regulated by copper availability, further implicating it in copper 
      delivery to Cox2. In order to place Coa6 in the Cox2 copper delivery pathway, we 
      performed a comprehensive genetic epistasis analysis in the yeast Saccharomyces 
      cerevisiae and found that simultaneous deletion of Coa6 and Sco2, a mitochondrial 
      copper metallochaperone, or Coa6 and Cox12/COX6B, a structural subunit of CcO, 
      completely abrogates Cox2 biogenesis. Unlike Coa6 deficient cells, copper 
      supplementation fails to rescue Cox2 levels of these double mutants. 
      Overexpression of Cox12 or Sco proteins partially rescues the coa6Delta phenotype, 
      suggesting their overlapping but non-redundant roles in copper delivery to Cox2. 
      These genetic data are strongly corroborated by biochemical studies demonstrating 
      physical interactions between Coa6, Cox2, Cox12 and Sco proteins. Furthermore, we 
      show that patient mutations in Coa6 disrupt Coa6-Cox2 interaction, providing the 
      biochemical basis for disease pathogenesis. Taken together, these results place 
      COA6 in the copper delivery pathway to CcO and, surprisingly, link it to a 
      previously unidentified function of CcO subunit Cox12 in Cox2 biogenesis.
CI  - (c) The Author 2015. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Ghosh, Alok
AU  - Ghosh A
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA.
FAU - Pratt, Anthony T
AU  - Pratt AT
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA.
FAU - Soma, Shivatheja
AU  - Soma S
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA.
FAU - Theriault, Sarah G
AU  - Theriault SG
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA.
FAU - Griffin, Aaron T
AU  - Griffin AT
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA.
FAU - Trivedi, Prachi P
AU  - Trivedi PP
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA.
FAU - Gohil, Vishal M
AU  - Gohil VM
AD  - Department of Biochemistry and Biophysics, Texas A&M University, College Station, 
      TX 77843, USA vgohil@tamu.edu.
LA  - eng
GR  - R01 GM111672/GM/NIGMS NIH HHS/United States
GR  - R01GM111672/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151215
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Carrier Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (SCO2 protein, S cerevisiae)
RN  - 0 (SCO2 protein, human)
RN  - 0 (Saccharomyces cerevisiae Proteins)
RN  - 789U1901C5 (Copper)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.14.99.1 (PTGS2 protein, human)
RN  - EC 1.9.3.- (cytochrome C oxidase subunit II)
RN  - EC 1.9.3.1 (COX6B1 protein, human)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Carrier Proteins/genetics/metabolism
MH  - Copper/metabolism
MH  - Cyclooxygenase 2/*biosynthesis/genetics/metabolism
MH  - Electron Transport Complex IV/biosynthesis/*genetics/metabolism
MH  - Humans
MH  - Mitochondria/metabolism
MH  - Mitochondrial Diseases/*genetics/metabolism
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Molecular Chaperones
MH  - Mutation
MH  - Phenotype
MH  - Saccharomyces cerevisiae/genetics/metabolism
MH  - Saccharomyces cerevisiae Proteins/genetics/metabolism
PMC - PMC4743686
EDAT- 2015/12/17 06:00
MHDA- 2016/12/15 06:00
PMCR- 2017/02/15
CRDT- 2015/12/17 06:00
PHST- 2015/08/21 00:00 [received]
PHST- 2015/12/07 00:00 [accepted]
PHST- 2015/12/17 06:00 [entrez]
PHST- 2015/12/17 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2017/02/15 00:00 [pmc-release]
AID - ddv503 [pii]
AID - 10.1093/hmg/ddv503 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2016 Feb 15;25(4):660-71. doi: 10.1093/hmg/ddv503. Epub 2015 Dec 
      15.