Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2.
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.
Chen
Z X
ZX
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Pervaiz
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000502:physiology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; C480024:COX5B protein, human; D003576:Electron Transport Complex IV