Functional effects of mutations in cytochrome c oxidase related to prostate cancer

Namslauer, Ida; Dietz, Marina S.; Brzezinski, Peter

doi:10.1016/j.bbabio.2011.02.005

Cited by 9 publications

(4 citation statements)

References 32 publications

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“…The alterations of COX in the pathogenesis of malignancies have been investigated in several studies. As the result of ROS injury accumulation, mutations of mtDNA-encoded subunits of COX (COX I to III) are well understood in a number of tumors, including CRC [ 19 , 20 ], prostate cancer [ 21 , 22 ], hepatocellular carcinoma [ 23 ] and myelodysplastic syndrome [ 24 ]. In addition to mtDNA-encoded COX subunits, genomic DNA-encoded subunits, especially COX V, are also studied in several tumor types.…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of cytochrome c oxidase subunit IV in colorectal cancer patients

Zhang¹,

Chen²,

Huang³

et al. 2016

aoms

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IntroductionPrevious studies have demonstrated that the expression of cytochrome c oxidase (COX) subunits encoded by mitochondrial DNA is elevated in colorectal cancer (CRC). However, the expression of nuclear DNA-encoded COX IV and its clinical significance have not yet been investigated in CRC.Material and methodsWe examined COX IV expression in paired CRC samples (cancer and pericancerous tissues) by quantitative real-time polymerase chain reaction (qPCR), Western blot and immunohistochemical staining and analyzed its clinical significance.ResultsqPCR and Western blot analyses showed that COX IV expression was significantly elevated at both the mRNA (p = 0.05) and protein levels in CRC tissue samples when compared with those in paired pericancerous tissues. Immunohistochemistry also revealed that COX IV expression was significantly increased in CRC tissues (p < 0.001). Association analyses showed that there was no significant association between COX IV expression and clinical parameters of CRC patients except for gender (p = 0.017). Moreover, we did not find any association between COX IV expression and overall survival or recurrence-free survival of CRC patients. Further analysis showed no significant relationship between the expression of COX IV and proliferating cell nuclear antigen (PCNA), a marker of cell proliferation.ConclusionsOur findings suggest that elevated COX IV expression may play an important role in colorectal carcinogenesis, but not in progression, which warrants further investigation in future studies.

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Section: Discussionmentioning

confidence: 99%

Expression and clinical significance of cytochrome c oxidase subunit IV in colorectal cancer patients

Zhang¹,

Chen²,

Huang³

et al. 2016

aoms

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“…1 For example, impairment of proton pumping function in mitochondria has been implicated in several serious human diseases. [2][3][4][5][6] There is also considerable interest in developing articial (bio)systems for pumping protons for various energy related applications. 7,8 Therefore, understanding the microscopic mechanism that ensures the vectorial nature of proton pumping is of fundamental, biomedical and practical signicance.…”

Section: Introductionmentioning

confidence: 99%

Microscopic basis for kinetic gating in cytochrome c oxidase: insights from QM/MM analysis

2015

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Understanding the mechanism of vectorial proton pumping in biomolecules requires establishing the microscopic basis for the regulation of both thermodynamic and kinetic features of the relevant proton transfer steps. For the proton pump cytochrome c oxidase, while the regulation of thermodynamic driving force for key proton transfers has been discussed in great detail, the microscopic basis for the control of proton transfer kinetics has been poorly understood. Here we carry out extensive QM/MM free energy simulations to probe the kinetics of relevant proton transfer steps and analyze the effects of local structure and hydration level. We show that protonation of the proton loading site (PLS, taken to be a propionate of heme a3) requires a concerted process in which a key glutamic acid (Glu286H) delivers the proton to the PLS while being reprotonated by an excess proton coming from the D-channel. The concerted nature of the mechanism is a crucial feature that enables the loading of the PLS before the cavity containing Glu286 is better hydrated to lower its pKa to experimentally measured range; the charged rather than dipolar nature of the process also ensures a tight coupling with heme a reduction, as emphasized by Siegbahn and Blomberg. In addition, we find that rotational flexibility of the PLS allows its protonation before that of the binuclear center (the site where oxygen gets reduced to water). Together with our recent study (P. Goyal, et al., Proc. Natl. Acad. Sci. USA, 110:18886-18891, 2013) that focused on the modulation of Glu286 pKa, the current work suggests a mechanism that builds in a natural sequence for the protonation of the PLS prior to that of the binuclear center. This provides microscopic support to the kinetic constraints revealed by kinetic network analysis as essential elements that ensure an efficient vectorial proton transport in cytochrome c oxidase.

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“…Cell respiratory growth profiles (Figure 2A) confirmed the respiratory-deficiency phenotype of the V380M and G384D point mutations. The revertants M380T and M380I (V380T and V380I, respectively) restored respiratory competence as, surprisingly, did the double mutant V380M/G384D [Figure 2A, see also (Namslauer et al, 2011)]. The inhibition of growth of V380M and G384D cells was not due to impaired expression of CcO, which was expressed above WT levels (3.2 and 2.6, respectively, compared to 2.4 nmol/gm wet weight in WT).…”

Section: Catalytic Activity and Redox Properties Of Wt And Mutant Yeast Ccomentioning

confidence: 90%

Electron Transfer Coupled to Conformational Dynamics in Cell Respiration

Reidelbach

Zimmer

Meunier

et al. 2021

Front. Mol. Biosci.

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Cellular respiration is a fundamental process required for energy production in many organisms. The terminal electron transfer complex in mitochondrial and many bacterial respiratory chains is cytochrome c oxidase (CcO). This converts the energy released in the cytochrome c/oxygen redox reaction into a transmembrane proton electrochemical gradient that is used subsequently to power ATP synthesis. Despite detailed knowledge of electron and proton transfer paths, a central question remains as to whether the coupling between electron and proton transfer in mammalian mitochondrial forms of CcO is mechanistically equivalent to its bacterial counterparts. Here, we focus on the conserved span between H376 and G384 of transmembrane helix (TMH) X of subunit I. This conformationally-dynamic section has been suggested to link the redox activity with the putative H pathway of proton transfer in mammalian CcO. The two helix X mutants, Val380Met (V380M) and Gly384Asp (G384D), generated in the genetically-tractable yeast CcO, resulted in a respiratory-deficient phenotype caused by the inhibition of intra-protein electron transfer and CcO turnover. Molecular aspects of these variants were studied by long timescale atomistic molecular dynamics simulations performed on wild-type and mutant bovine and yeast CcOs. We identified redox- and mutation-state dependent conformational changes in this span of TMH X of bovine and yeast CcOs which strongly suggests that this dynamic module plays a key role in optimizing intra-protein electron transfers.

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Functional effects of mutations in cytochrome c oxidase related to prostate cancer

Cited by 9 publications

References 32 publications

Expression and clinical significance of cytochrome c oxidase subunit IV in colorectal cancer patients

Expression and clinical significance of cytochrome c oxidase subunit IV in colorectal cancer patients

Microscopic basis for kinetic gating in cytochrome c oxidase: insights from QM/MM analysis

Electron Transfer Coupled to Conformational Dynamics in Cell Respiration

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