The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the CuB and CuA sites, respectively. Biogenesis of these two copper sites of CcO occurs separately and requires a number of evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Pathogenic mutations in some of the proteins of the copper delivery pathway, such as SCO1, SCO2, and COA6, have been shown to cause fatal infantile human disorders, highlighting the biomedical significance of understanding copper delivery mechanisms to CcO. While two decades of studies have provided a clearer picture regarding the biochemical roles of SCO1 and SCO2 proteins, some discrepancy exists regarding the function of COA6, the new member of this pathway. Initial genetic and biochemical studies have linked COA6 with copper delivery to COX2 and follow-up structural and functional studies have shown that it is specifically required for the biogenesis of the CuA site by acting as a disulfide reductase of SCO and COX2 proteins. Its role as a copper metallochaperone has also been proposed. Here, we critically review the recent literature regarding the molecular function of COA6 in CuA biogenesis.

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Molecular characterization of a complex of Apoptosis Inducing Factor 1 (AIFM1) with cytochrome c oxidase of the mitochondrial respiratory chain

10.1101/2021.03.31.437858 ◽

2021 ◽

Author(s):

Johannes F Hevler ◽

Riccardo Zenezini Chiozzi ◽

Alfredo Cabrera-Orefice ◽

Ulrich Brandt ◽

Susanne Arnold ◽

...

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Respiratory Chain ◽

Structural Model ◽

Direct Electron Transfer ◽

Mitochondrial Respiratory Chain ◽

Structural Restraints ◽

Apoptosis Inducing Factor

Combining mass spectrometry based chemical cross-linking and complexome profiling, we analyzed the interactome of heart mitochondria. We focused on complexes of oxidative phosphorylation and found that dimeric apoptosis inducing factor 1 (AIFM1) forms a defined complex with ~10% of monomeric cytochrome c oxidase (COX), but hardly interacts with respiratory chain supercomplexes. Multiple AIFM1 inter-crosslinks engaging six different COX subunits provided structural restraints to build a detailed atomic model of the COX-AIFM12 complex. Application of two complementary proteomic approaches thus provided unexpected insight into the macromolecular organization of the mitochondrial complexome. Our structural model excludes direct electron transfer between AIFM1 and COX. Notably however, the binding site of cytochrome c remains accessible allowing formation of a ternary complex. The discovery of the previously overlooked COX-AIFM12 complex and clues provided by the structural model hint at a role of AIFM1 in OXPHOS biogenesis and in programmed cell death.

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Short-Term Ultramicronized Palmitoylethanolamide Therapy in Patients with Myasthenia Gravis: a Pilot Study to Possible Future Implications of Treatment

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190131121827 ◽

2019 ◽

Vol 18 (3) ◽

pp. 232-238 ◽

Cited By ~ 5

Author(s):

Emanuela Onesti ◽

Vittorio Frasca ◽

Marco Ceccanti ◽

Giorgio Tartaglia ◽

Maria Cristina Gori ◽

...

Keyword(s):

Pilot Study ◽

Myasthenia Gravis ◽

Repetitive Nerve Stimulation ◽

Beneficial Effects ◽

Antibody Titers ◽

The Stability ◽

Ultramicronized Palmitoylethanolamide ◽

Open Pilot

Background: The cannabinoid system may be involved in the humoral mechanisms at the neuromuscular junction. Ultramicronized-palmitoylethanolamide (μm-PEA) has recently been shown to reduce the desensitization of Acetylcholine (ACh)-evoked currents in denervated patients modifying the stability of ACh receptor (AChR) function. <p> Objective: To analyze the possible beneficial effects of μm-PEA in patients with myasthenia gravis (MG) on muscular fatigue and neurophysiological changes. <p> Method: The duration of this open pilot study, which included an intra-individual control, was three weeks. Each patient was assigned to a 1-week treatment period with μm-PEA 600 mg twice a day. A neurophysiological examination based on repetitive nerve stimulation (RNS) of the masseteric and the axillary nerves was performed, and the quantitative MG (QMG) score was calculated in 22 MG patients every week in a three-week follow-up period. AChR antibody titer was investigated to analyze a possible immunomodulatory effect of PEA in MG patients. <p> Results: PEA had a significant effect on the QMG score (p=0.03418) and on RNS of the masseteric nerve (p=0.01763), thus indicating that PEA reduces the level of disability and decremental muscle response. Antibody titers did not change significantly after treatment. <p> Conclusion: According to our observations, μm-PEA as an add-on therapy could improve muscular response to fatigue in MG. The possible modulation of AChR currents as a means of eliciting a direct effect from PEA on the conformation of ACh receptors should be investigated. The co-role of cytokines also warrants an analysis. Given the rapidity and reversibility of the response, we suppose that PEA acts directly on AChR, though further studies are needed to confirm this hypothesis.

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The role of the K-channel and the active-site tyrosine in the catalytic mechanism of cytochrome c oxidase

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2016.04.014 ◽

2016 ◽

Vol 1857 ◽

pp. e2

Author(s):

Vivek Sharma ◽

Mårten Wikström

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Active Site ◽

Catalytic Mechanism ◽

K Channel ◽

Active Site Tyrosine

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Cytochrome c Oxidase Rather than Cytochrome c is a Major Determinant of Mitochondrial Respiratory Capacity in Skeletal Muscle of Aged Rats: Role of Carnitine and Lipoic Acid

Rejuvenation Research ◽

10.1089/rej.2007.0541 ◽

2007 ◽

Vol 10 (3) ◽

pp. 311-326 ◽

Cited By ~ 4

Author(s):

Jayavelu Tamilselvan ◽

Kumarasamy Sivarajan ◽

Muthuswamy Anusuyadevi ◽

Chinnakkannu Panneerselvam

Keyword(s):

Skeletal Muscle ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Lipoic Acid ◽

Major Determinant ◽

Aged Rats ◽

Respiratory Capacity ◽

Mitochondrial Respiratory

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Role of subunit III and its lipids in the molecular mechanism of cytochrome c oxidase

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2015.04.007 ◽

2015 ◽

Vol 1847 (8) ◽

pp. 690-697 ◽

Cited By ~ 18

Author(s):

Vivek Sharma ◽

Pauliina Ala-Vannesluoma ◽

Ilpo Vattulainen ◽

Mårten Wikström ◽

Tomasz Róg

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Molecular Mechanism ◽

Subunit Iii

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Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

Journal of Molecular Medicine ◽

10.1007/s00109-020-01905-y ◽

2020 ◽

Vol 98 (5) ◽

pp. 651-657 ◽

Cited By ~ 4

Author(s):

Rabia Ramzan ◽

Sebastian Vogt ◽

Bernhard Kadenbach

Keyword(s):

Cytochrome C ◽

Cytochrome C Oxidase ◽

Healthy Individuals

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The role of an evolutionarily conserved cis-proline in the thioredoxin-like domain of human class Alpha glutathione transferase A1-1

Biochemical Journal ◽

10.1042/bj20021765 ◽

2003 ◽

Vol 372 (1) ◽

pp. 241-246 ◽

Cited By ~ 24

Author(s):

Chris NATHANIEL ◽

Louise A. WALLACE ◽

Jonathan BURKE ◽

Heini W. DIRR

Keyword(s):

Glutathione Transferase ◽

Conformational Stability ◽

Wild Type ◽

Catalytic Function ◽

Evolutionarily Conserved ◽

Glutathione S Transferases ◽

Equilibrium Unfolding ◽

The Stability ◽

Unfolding Kinetics

The thioredoxin-like fold has a βαβαββα topology, and most proteins/domains with this fold have a topologically conserved cis-proline residue at the N-terminus of β-strand 3. This residue plays an important role in the catalytic function and stability of thioredoxin-like proteins, but is reported not to contribute towards the stability of glutathione S-transferases (GSTs) [Allocati, Casalone, Masulli, Caccarelli, Carletti, Parker and Di Ilio (1999) FEBS Lett. 445, 347–350]. In order to further address the role of the cis-proline in the structure, function and stability of GSTs, cis-Pro-56 in human GST (hGST) A1-1 was replaced with a glycine, and the properties of the P56G mutant were compared with those of the wild-type protein. Not only was the catalytic function of the mutant dramatically reduced, so was its conformational stability, as indicated by equilibrium unfolding and unfolding kinetics experiments with urea as denaturant. These findings are discussed in the context of other thioredoxin-like proteins.

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