Oxidative Phosphorylation Enzymes in Normal and Neoplastic Cell Growth

Abstract

Cancer cells, despite growing aerobically, have the propension to utilize the glycolytic pathway as energy source. This biochemical phenotype is accompanied by a decreased content of mitochondria and, paradoxically, by enhanced transcription of nuclear and mitochondrial-encoded genes for the enzymes of oxidative phosphorylation (OXPHOS). The role of OXPHOS enzymes in normal and neoplastic cell growth has been studied in liver regeneration and human hepatocellular carcinoma. In early liver regeneration characterized by active mtDNA replication, a decrease in the content and activity of ATP synthase occurs while transcription of the ATPsynβ nuclear gene is activated. Translation of ATP synthase subunits seems, on the contrary, to be less effective in this phase. In the second replicative phase of liver regeneration, the repression of ATPsynβ translation is relieved and normal cell growth starts. In this replicative phase the recovery of the liver mass appears to be directly related to the recovery of the OXPHOS capacity. Mitochondria isolated from biopsies of human hepatocellular carcinoma exhibit a decreased rate of respiratory ATP synthesis (OXPHOS) and a decreased ATPase activity. The decline in the activity of the ATP synthase is found to be associated with a decreased content of the ATPsynβ in the inner mitochondrial membrane. In neoplastic tissue the ATPase inhibitor protein (IF₁) is overexpressed. This could contribute to prevent hydrolysis of glycolytic ATP in cancer cells. A peptide segment of IF₁ (IF₁-(42-58)-peptide), constructed by chemical synthesis, proved to be equally effective as IF₁ in inhibiting the ATPase activity of the ATP synthase complex in the mitochondrial membrane deprived of IF₁. The synthetic peptide might turn out to be a useful tool to develop immunological approaches for the control of neoplastic growth.