Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2

• Published in: Cell death and differentiation Vol. 17; no. 3; pp. 408 - 420
• Main Authors: Chen, Z X, Pervaiz, S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2010
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Sequence; Animals; Cancer; Cell death; Cell Line, Tumor; Cell Respiration - physiology; Cytochrome; Electron Transport Complex IV - genetics; Electron Transport Complex IV - metabolism; Enzymes; Genomes; Humans; Hypotheses; Hypoxia; Localization; Metabolism; Mitochondria; Mitochondria - metabolism; Molecular Sequence Data; Neoplasms - genetics; Neoplasms - metabolism; Oxidation-Reduction; Oxidative Stress; Physiology; Protein Subunits - genetics; Protein Subunits - metabolism; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive Oxygen Species - metabolism; Respiration; Singapore
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2009.132

Bcl-2 has been shown to promote survival of cancer cells by maintaining a slight pro-oxidant state through elevated mitochondrial respiration during basal conditions. On oxidative stress, Bcl-2 moderates mitochondrial respiration through cytochrome c oxidase (COX) activity to prevent an excessive buildup of reactive oxygen species (ROS) by-production from electron transport activities. However, the underlying molecular mechanism(s) of Bcl-2-mediated ROS regulation and its impact on carcinogenesis remain unclear. In this study, we show that Bcl-2 expression positively influences the targeting of nuclear-encoded COX Va and Vb to the mitochondria of cancer cells. In addition, evidence is presented in support of a protein-protein interaction between COX Va and Bcl-2, involving the BH2 domain of Bcl-2. Interestingly, episodes of serum withdrawal, glucose deprivation or hypoxia aimed at inducing early oxidative stress triggered Bcl-2-overexpressing cells to preserve mitochondrial levels of COX Va while depressing COX Vb, whereas the reverse was observed in mock-transfected cells. The unique manner in which Bcl-2 adjusted COX subunits during these physiological stress triggers had a profound impact on the resultant decrease in COX activity and maintenance of mitochondrial ROS levels, thus delineating a novel mechanism for the homeostatic role of Bcl-2 in the redox biology and metabolism of cancer cells.