Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Sep 15;53(6):1252-63.
doi: 10.1016/j.freeradbiomed.2012.07.021. Epub 2012 Jul 25.

Cytochrome c oxidase dysfunction in oxidative stress

Affiliations
Review

Cytochrome c oxidase dysfunction in oxidative stress

Satish Srinivasan et al. Free Radic Biol Med. .

Abstract

Cytochrome c oxidase (CcO) is the terminal oxidase of the mitochondrial electron transport chain. This bigenomic enzyme in mammals contains 13 subunits of which the 3 catalytic subunits are encoded by the mitochondrial genes. The remaining 10 subunits with suspected roles in the regulation, and/or assembly, are coded by the nuclear genome. The enzyme contains two heme groups (heme a and a3) and two Cu(2+) centers (Cu(2+) A and Cu(2+) B) as catalytic centers and handles more than 90% of molecular O(2) respired by the mammalian cells and tissues. CcO is a highly regulated enzyme which is believed to be the pacesetter for mitochondrial oxidative metabolism and ATP synthesis. The structure and function of the enzyme are affected in a wide variety of diseases including cancer, neurodegenerative diseases, myocardial ischemia/reperfusion, bone and skeletal diseases, and diabetes. Despite handling a high O(2) load the role of CcO in the production of reactive oxygen species still remains a subject of debate. However, a volume of evidence suggests that CcO dysfunction is invariably associated with increased mitochondrial reactive oxygen species production and cellular toxicity. In this paper we review the literature on mechanisms of multimodal regulation of CcO activity by a wide spectrum of physiological and pathological factors. We also review an array of literature on the direct or indirect roles of CcO in reactive oxygen species production.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Regulation of Cytochrome C Oxidase. Cells control CcO function by regulating both protein content and enzyme activity. Co ordinated expression of subunits, their assembly into complexes and supercomplexes provide a global control over protein levels of the enzyme. Differential cell and tissue specific expression of subunit isoforms and their relative abundance are used to change enzyme composition and alter kinetic properties of CcO activity in accordance with oxidative capacity of the tissues. Rapid adaptation to cellular bioenergetic requirements is brought about by binding small molecules like ATP/ADP, di-iodo thyronine, NO and by phosphorylation of specific subunits that either increase or decrease CcO activity. The multimodal regulation of CcO activity is summarized in this figure.
Figure 2
Figure 2
Factors which cause dysfunction of Cytochrome C Oxidase. Multiple factors affect CcO function leading to mitochondrial stress and dysfunction. Genetic mutations of subunits and assembly factors are responsible for significant decrease in fully assembled complexes. Environmental changes such as hypoxia induce phosphorylation which either increase the activity or decrease activity by targeting the subunits for degradation. Many xenobiotics act by directly binding to active site heme and inhibit enzyme activity. Dysfunctional CcO contributes greatly to oxidative stress by increasing ROS production, ATP depletion and lactic acidosis.
Figure 3
Figure 3
Mechanism of ethanol, ischemia and drug induced mitochondrial ROS production. Results show that ethanol, myocardial ischemia and drugs such as doxorubicin cause CcO dysfunction and induce ROS production. In the case of ethanol induced toxicity, increased mitochondrial superoxide anion reacts with NO to form the highly reactive peroxynitrite which covalently modifies proteins and Fe S centers.

Similar articles

Cited by

References

    1. Acin-Perez R, Fernandez-Silva P, Peleato ML, Perez-Martos A, Enriquez JA. Respiratory active mitochondrial supercomplexes. Mol. Cell. 2008;32:529–539. - PubMed
    1. Acin-Perez R, Gatti DL, Bai Y, Manfredi G. Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. Cell Metab. 2011;13:712–719. - PMC - PubMed
    1. Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G. Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab. 2009;9:265–276. - PMC - PubMed
    1. Allen LA, Zhao XJ, Caughey W, Poyton RO. Isoforms of yeast cytochrome c oxidase subunit V affect the binuclear reaction center and alter the kinetics of interaction with the isoforms of yeast cytochrome c. J Biol Chem. 1995;270:110–118. - PubMed
    1. Andreyev AY, Kushnareva YE, Starkov AA. Mitochondrial metabolism of reactive oxygen species. Biochemistry. Biokhimii Inverted Question Marka Inverted Question Mark. 2005;70:200–214. - PubMed

Publication types

LinkOut - more resources