Electron transfer from reduced cytochrome c to molecular oxygen

Stable Identifier
R-HSA-163214
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Complex IV (COX, cytochrome c oxidase) contains the hemeprotein cytochrome a and a3. It also contains copper atoms which undergo a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. A bimetallic centre containing a copper atom and a heme-linked iron protein binds oxygen after 4 electrons have been picked up. Water, the final product of oxygen reduction, is then released. Oxygen is the final electron acceptor in the respiratory chain. The overall reaction can be summed as

4Cyt c (red.) + 12H+ (in) + O2 = 4Cyt c (ox.) + 2H2O + 8H+ (out)

Four protons are taken up from the matrix side of the membrane to form the water (scalar protons). Wikstrom (1977) suggests 4 protons are additionally transferred out from the matrix to the intermembrane space.

COX ancillary proteins mediate membrane insertion, catalytic core processing, copper transport and insertion into core subunits and heme A biosynthesis (Stilburek et al. 2006, Fontanesi et al. 2006, Soto et al. 2012). To date, all Mendelian disorders presenting COX deficiency have been assigned to mutations in ancillary factors, with the exception of an infantile encephalomyopathy caused by a defective COX6B1 and an exocrine pancreatic insufficiency caused by a defective COX4I2 gene (Soto et al. 2012). Balsa et al have shown that NDUFA4, formerly considered to be a constituent of NADH dehydrogenase (Complex I), is instead a component of the cytochrome c oxidase (CIV) (Balsa et al. 2012). Patients with NDUFA4 mutations display COX deficiencies (Pitceathly et al. 2013).

Carbon monoxide (CO) readily inhibits oxygen consumption by mitochondrial cytochrome oxidase. This inhibition is responsible for much of its toxicity when it is applied externally to the body. However, CO has been implicated in normal cellular signalling, especially in anti-inflammatory effects. The addition of antioxidants or inhibition of complex III of the electron transport chain by antimycin A attenuates the inhibitory effects of CO on lipopolysaccharide (LPS)-induced NLRP3 formation and TNF-alpha secretion, and blocked CO-induced p38 MAPK phosphorylation. These effects may be mediated via inhibition of cytochrome c oxidase and its generation of mitochondrial reactive oxygen species (Alonso et al, 2003; Zuckerbraun et al, 2007; Cooper and Brown, 2008; Jung et al, 2014; Ishigami et al, 2017).

Literature References
PubMed ID Title Journal Year
16760263 Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process

Fontanesi, F, Soto, IC, Horn, D, Barrientos, A

Am. J. Physiol., Cell Physiol. 2006
11340051 Structures and proton-pumping strategies of mitochondrial respiratory

Schultz, BE, Chan, SI

Annu Rev Biophys Biomol Struct 2001
23746447 NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease

Pitceathly, RD, Rahman, S, Wedatilake, Y, Polke, JM, Cirak, S, Foley, AR, Sailer, A, Hurles, ME, Stalker, J, Hargreaves, I, Woodward, CE, Sweeney, MG, Muntoni, F, Houlden, H, Taanman, JW, Hanna, MG

Cell Rep 2013
22902835 NDUFA4 is a subunit of complex IV of the mammalian electron transport chain

Balsa, E, Marco, R, Perales-Clemente, E, Szklarczyk, R, Calvo, E, Landázuri, MO, Enríquez, JA

Cell Metab. 2012
15223 Proton pump coupled to cytochrome c oxidase in mitochondria

Wikstrom, MK

Nature 1977
7979252 Energy transduction by cytochrome complexes in mitochondrial and bacterial

Trumpower, BL, Gennis, RB

Annu Rev Biochem 1994
17298220 Biogenesis of eukaryotic cytochrome c oxidase

Stiburek, L, Hansikova, H, Tesarova, M, Cerna, L, Zeman, J

Physiol Res 2006
21958598 Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core

Soto, IC, Fontanesi, F, Liu, J, Barrientos, A

Biochim. Biophys. Acta 2012
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Event Information
Catalyst Activity

cytochrome-c oxidase activity of Cytochrome c oxidase [mitochondrial inner membrane]

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