scholarly journals What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?

2020 ◽  
Vol 21 (19) ◽  
pp. 6983
Author(s):  
Shadi Maghool ◽  
Michael T. Ryan ◽  
Megan J. Maher
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Molecular Mechanisms ◽  
Intermembrane Space ◽  
Copper Binding ◽  
Transport Chain ◽  
Assembly Factor ◽  
Controversial Area ◽  
Thiol Oxidoreductase ◽  
Assembly Activity

Complex IV (cytochrome c oxidase; COX) is the terminal complex of the mitochondrial electron transport chain. Copper is essential for COX assembly, activity, and stability, and is incorporated into the dinuclear CuA and mononuclear CuB sites. Multiple assembly factors play roles in the biogenesis of these sites within COX and the failure of this intricate process, such as through mutations to these factors, disrupts COX assembly and activity. Various studies over the last ten years have revealed that the assembly factor COA6, a small intermembrane space-located protein with a twin CX9C motif, plays a role in the biogenesis of the CuA site. However, how COA6 and its copper binding properties contribute to the assembly of this site has been a controversial area of research. In this review, we summarize our current understanding of the molecular mechanisms by which COA6 participates in COX biogenesis.

scholarly journals Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase

2015 ◽  
Vol 26 (13) ◽  
pp. 2385-2401 ◽  
Author(s):  
Manuela Bode ◽  
Michael W. Woellhaf ◽  
Maria Bohnert ◽  
Martin van der Laan ◽  
Frederik Sommer ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Specific Binding ◽  
Hydrophobic Surface ◽  
Cysteine Residue ◽  
Oxidative Modification ◽  
Intermembrane Space ◽  
Copper Binding ◽  
C Protein ◽  
Copper Transfer

Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase.

scholarly journals Mitochondrial COA7 is a heme-binding protein involved in the early stages of complex IV assembly.

2021 ◽  
Author(s):  
Luke E Formosa ◽  
Shadi Maghool ◽  
Alice J. Sharpe ◽  
Boris Reljic ◽  
Linden Muellner-Wong ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Disulfide Bonds ◽  
Initial Step ◽  
Intermembrane Space ◽  
Heme Binding ◽  
Complex Iv ◽  
Assembly Factor ◽  
Mitochondrial Intermembrane Space ◽  
Methionine Residues

Cytochrome c oxidase assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked in patients to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here we show that the absence of COA7 leads to arrest of the complex IV assembly pathway at the initial step where the COX1 module is built, which requires incorporation of copper and heme cofactors. In solution, purified COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. Surprisingly, the crystal structure of COA7, determined to 2.4 angstroms resolution, reveals a banana-shaped molecule composed of five helix-turn-helix repeats, tethered by disulfide bonds, with a structure entirely distinct from proteins with characterized heme binding activities. We therefore propose a role for COA7 in heme binding/chaperoning in the mitochondrial intermembrane space, this activity being crucial for and providing a missing link in complex IV biogenesis.

scholarly journals Regulation of Cytochrome c Oxidase by Natural Compounds Resveratrol, (–)-Epicatechin, and Betaine

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1346
Author(s):  
Icksoo Lee
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Model Systems ◽  
Health Improvement ◽  
Published Data ◽  
Mitochondrial Electron Transport Chain ◽  
Naturally Occurring ◽  
Transport Chain ◽  
Wide Range ◽  
Experimental Model Systems

Numerous naturally occurring molecules have been studied for their beneficial health effects. Many compounds have received considerable attention for their potential medical uses. Among them, several substances have been found to improve mitochondrial function. This review focuses on resveratrol, (–)-epicatechin, and betaine and summarizes the published data pertaining to their effects on cytochrome c oxidase (COX) which is the terminal enzyme of the mitochondrial electron transport chain and is considered to play an important role in the regulation of mitochondrial respiration. In a variety of experimental model systems, these compounds have been shown to improve mitochondrial biogenesis in addition to increased COX amount and/or its enzymatic activity. Given that they are inexpensive, safe in a wide range of concentrations, and effectively improve mitochondrial and COX function, these compounds could be attractive enough for possible therapeutic or health improvement strategies.

scholarly journals Cytochrome c oxidase assembly factor Surf1: Candidate for heme a insertion into subunit I

2012 ◽  
Vol 1817 ◽  
pp. S70
Author(s):  
S. Schimo ◽  
A. Hannappel ◽  
F.A. Bundschuh ◽  
C. Glaubnitz ◽  
K.M. Pos ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Assembly Factor

scholarly journals Effects of L-Malate on Mitochondrial Oxidoreductases in Liver of Aged Rats

2011 ◽  
pp. 329-336 ◽  
Author(s):  
J.-L. WU ◽  
Q.-P. WU ◽  
Y.-P. PENG ◽  
J.-M. ZHANG
Keyword(s):  
Electron Transport ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Electron Transport Chain ◽  
Nadh Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Radical Scavenger ◽  
Aged Rats ◽  
Transport Chain ◽  
Nadh Cytochrome

Accumulation of oxidative damage has been implicated to be a major causative factor in the decline in physiological functions that occur during the aging process. The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and aging. L-malate, a tricarboxylic acid cycle intermediate, plays an important role in transporting NADH from cytosol to mitochondria for energy production. Previous studies in our laboratory reported L-malate as a free radical scavenger in aged rats. In the present study we focused on the effect of L-malate on the activities of electron transport chain in young and aged rats. We found that mitochondrial membrane potential (MMP) and the activities of succinate dehydrogenase, NADH-cytochrome c oxidoreductase and cytochrome c oxidase in liver of aged rats were significantly decreased when compared to young control rats. Supplementation of L-malate to aged rats for 30 days slightly increased MMP and improved the activities of NADH-dehydrogenase, NADH-cytochrome c oxidoreductase and cytochrome c oxidase in liver of aged rats when compared with aged control rats. In young rats, L-malate administration increased only the activity of NADH-dehydrogenase. Our result suggested that L-malate could improve the activities of electron transport chain enzymes in aged rats

scholarly journals Co-ordinate decrease in the expression of the mitochondrial genome and nuclear genes for mitochondrial proteins in the lactation-induced mitochondrial hypotrophy of rat brown fat

1995 ◽  
Vol 308 (3) ◽  
pp. 749-752 ◽  
Author(s):  
I Martin ◽  
M Giralt ◽  
O Viñas ◽  
R Iglesias ◽  
T Mampel ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Mitochondrial Genome ◽  
Cytochrome C Oxidase ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Relative Content ◽  
Nuclear Genes ◽  
Mitochondrial Proteins ◽  
Mrna Levels ◽  
Brown Adipose

The relative abundance of the mitochondrial-encoded mRNAs for cytochrome c oxidase subunit II and NADH dehydrogenase subunit I was lower in brown adipose tissue (BAT) from lactating rats than in virgin controls. This decrease was in parallel with a significant decrease in mitochondrial 16 S rRNA levels and in the relative content of mitochondrial DNA in the tissue. BAT from lactating rats showed lowered mRNA expression of the nuclear-encoded genes for the mitochondrial uncoupling protein, subunit IV of cytochrome c oxidase and the adenine nucleotide translocase isoforms ANT1 and ANT2, whereas mRNA levels for the ATP synthase beta-subunit were unchanged. However, the relative content of this last protein was lower in BAT mitochondria from lactating rats than in virgin controls. It is concluded that lactation-induced mitochondrial hypotrophy in BAT is associated with a co-ordinate decrease in the expression of the mitochondrial genome and nuclear genes for mitochondrial proteins. This decrease is caused by regulatory events acting at different levels, including pre- and post-transcriptional regulation. BAT appears to be a useful model with which to investigate the molecular mechanisms involved in the co-ordination of the expression of the mitochondrial and nuclear genomes during mitochondrial biogenesis.

scholarly journals C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved inbc1Complex Assembly and Supercomplex Stabilization

2015 ◽  
Vol 35 (7) ◽  
pp. 1139-1156 ◽  
Author(s):  
Marjorie Desmurs ◽  
Michelangelo Foti ◽  
Etienne Raemy ◽  
Frédéric Maxime Vaz ◽  
Jean-Claude Martinou ◽  
...  
Keyword(s):  
Intermembrane Space ◽  
Core Complex ◽  
Mitochondrial Inner Membrane ◽  
Transport Chain ◽  
Mammalian Mitochondria ◽  
Assembly Factor ◽  
Subsequent Elimination ◽  
Inner Membrane Protein ◽  
Selection Of ◽  
Higher Sensitivity

Mammalian mitochondria may contain up to 1,500 different proteins, and many of them have neither been confidently identified nor characterized. In this study, we demonstrated that C11orf83, which was lacking experimental characterization, is a mitochondrial inner membrane protein facing the intermembrane space. This protein is specifically associated with thebc1complex of the electron transport chain and involved in the early stages of its assembly by stabilizing thebc1core complex. C11orf83 displays some overlapping functions with Cbp4p, a yeastbc1complex assembly factor. Therefore, we suggest that C11orf83, now called UQCC3, is the functional human equivalent of Cbp4p. In addition, C11orf83 depletion in HeLa cells caused abnormal crista morphology, higher sensitivity to apoptosis, a decreased ATP level due to impaired respiration and subtle, but significant, changes in cardiolipin composition. We showed that C11orf83 binds to cardiolipin by its α-helices 2 and 3 and is involved in the stabilization ofbc1complex-containing supercomplexes, especially the III2/IV supercomplex. We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization, suggesting a role in the selection of cells with damaged mitochondria for their subsequent elimination by apoptosis, as previously described for OPA1.

scholarly journals Substrate Recognition by AAA+ ATPases: Distinct Substrate Binding Modes in ATP-Dependent Protease Yme1 of the Mitochondrial Intermembrane Space

2007 ◽  
Vol 27 (7) ◽  
pp. 2476-2485 ◽  
Author(s):  
Martin Graef ◽  
Georgeta Seewald ◽  
Thomas Langer
Keyword(s):  
Molecular Mechanisms ◽  
Substrate Binding ◽  
Substrate Recognition ◽  
Intermembrane Space ◽  
Binding Modes ◽  
General Role ◽  
Mitochondrial Inner Membrane ◽  
Assembly Factor ◽  
Substrate Binding Sites ◽  
Energy Dependent

ABSTRACT The energy-dependent proteolysis of cellular proteins is mediated by conserved proteolytic AAA+ complexes. Two such machines, the m- and i-AAA proteases, are present in the mitochondrial inner membrane. They exert chaperone-like properties and specifically degrade nonnative membrane proteins. However, molecular mechanisms of substrate engagement by AAA proteases remained elusive. Here, we define initial steps of substrate recognition and identify two distinct substrate binding sites in the i-AAA protease subunit Yme1. Misfolded polypeptides are recognized by conserved helices in proteolytic and AAA domains. Structural modeling reveals a lattice-like arrangement of these helices at the surface of hexameric AAA protease ring complexes. While helices within the AAA domain apparently play a general role for substrate binding, the requirement for binding to surface-exposed helices within the proteolytic domain is determined by the folding and membrane association of substrates. Moreover, an assembly factor of cytochrome c oxidase, Cox20, serves as a substrate-specific cofactor during proteolysis and modulates the initial interaction of nonassembled Cox2 with the protease. Our findings therefore reveal the existence of alternative substrate recognition pathways within AAA proteases and shed new light on molecular mechanisms ensuring the specificity of proteolysis by energy-dependent proteases.

scholarly journals Coa2 Is an Assembly Factor for Yeast Cytochrome c Oxidase Biogenesis That Facilitates the Maturation of Cox1

2008 ◽  
Vol 28 (16) ◽  
pp. 4927-4939 ◽  
Author(s):  
Fabien Pierrel ◽  
Oleh Khalimonchuk ◽  
Paul A. Cobine ◽  
Megan Bestwick ◽  
Dennis R. Winge
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Proteolytic Activity ◽  
Yeast Mitochondria ◽  
Early Step ◽  
Rapid Degradation ◽  
Respiratory Deficiency ◽  
The Matrix ◽  
Assembly Factor

ABSTRACT The assembly of cytochrome c oxidase (CcO) in yeast mitochondria is dependent on a new assembly factor designated Coa2. Coa2 was identified from its ability to suppress the respiratory deficiency of coa1Δ and shy1Δ cells. Coa1 and Shy1 function at an early step in maturation of the Cox1 subunit of CcO. Coa2 functions downstream of the Mss51-Coa1 step in Cox1 maturation and likely concurrent with the Shy1-related heme a 3 insertion into Cox1. Coa2 interacts with Shy1. Cells lacking Coa2 show a rapid degradation of newly synthesized Cox1. Rapid Cox1 proteolysis also occurs in shy1Δ cells, suggesting that in the absence of Coa2 or Shy1, Cox1 forms an unstable conformer. Overexpression of Cox10 or Cox5a and Cox6 or attenuation of the proteolytic activity of the m-AAA protease partially restores respiration in coa2Δ cells. The matrix-localized Coa2 protein may aid in stabilizing an early Cox1 intermediate containing the nuclear subunits Cox5a and Cox6.

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