No abstract

Oxidative phosphorylation within the inner mitochondrial membrane generates the majority of cellular adenosine triphosphate (ATP) required for normal physiological functions (including regulation of cell volume and solute concentration, maintenance of cellular architecture, and synthesis of essential macromolecules). Its efficient functioning depends on the maintenance of an electrochemical gradient and is tightly coupled to the energetic demands of the cell and/or tissue. Commitment to and completion of the cell division cycle are sensitive to changes in the availability of mitochondrially derived ATP, although the relationship between cell cycle and mitochondrial physiology is poorly understood. Using vital, mitochondrial-specific fluorochromes to differentiate between mitochondrial mass (10-N-nonyl acridine orange) and mitochondrial membrane potential (Rhodamine 123), together with a quantification of total cellular ATP levels, it was possible to generate profiles of these mitochondrial characteristics in HL-60 cells at different stages of their cell cycle. The data suggest that the availability of ATP changes in a cell cycle-specific manner and cannot be predicted by changes in mitochondrial mass or membrane potential. Furthermore, transition points in the cell cycle where ATP availability is low with respect to the amount of functional inner mitochondrial membrane have been observed. We suggest that these cell cycle phase transitions are sensitive to inhibition of mitochondrial activity because the basal levels of available ATP at these points are nearer to a theoretical "minimal threshold" below which cell cycle progression is inhibited.

Alterations in the biochemistry of mitochondria have been associated with cell transformation and the acquisition of drug resistance to certain chemotherapeutic agents, suggesting that mitochondria may play a supportive role for the cancer cell phenotype. Mitochondria are multifunctional organelles that contribute to the cellular adenosine triphosphate (ATP) pool and cellular redox balance through the production of reactive oxygen intermediates (ROI). Our laboratory has focused on these mitochondrial functions in the context of cancer cell physiology to evaluate the potential role of mitochondria as controllers of tumour cell proliferation. Low concentrations of ROI have been implicated as messengers in intracellular signal transduction mechanisms; thus an imbalance of ROI production from the mitochondria may support cancer cell growth. In addition, suppression of mitochondrial ATP production can halt cell cycle progression at two energetic checkpoints, suggesting that the use of tumor-selective agents to reduce ATP production may offer a therapeutic target for cancer growth control.