Abstract
The bioenergetics of IF1 transiently silenced cancer cells has been extensively investigated, but the role of IF1 (the natural inhibitor protein of F1F0-ATPase) in cancer cell metabolism is still uncertain. To shed light on this issue, we established a method to prepare stably IF1-silenced human osteosarcoma clones and explored the bioenergetics of IF1 null cancer cells. We showed that IF1-silenced cells proliferate normally, consume glucose, and release lactate as controls do, and contain a normal steady-state ATP level. However, IF1-silenced cells displayed an enhanced steady-state mitochondrial membrane potential and consistently showed a reduced ADP-stimulated respiration rate. In the parental cells (i.e. control cells containing IF1) the inhibitor protein was found to be associated with the dimeric form of the ATP synthase complex, therefore we propose that the interaction of IF1 with the complex either directly, by increasing the catalytic activity of the enzyme, or indirectly, by improving the structure of mitochondrial cristae, can increase the oxidative phosphorylation rate in osteosarcoma cells grown under normoxic conditions.
Highlights
The role of the inhibitor factor, IF1, of the F1F0-ATPase complex has not been fully defined
In the parental cells the inhibitor protein was found to be associated with the dimeric form of the ATP synthase complex, we propose that the interaction of IF1 with the complex either directly, by increasing the catalytic activity of the enzyme, or indirectly, by improving the structure of mitochondrial cristae, can increase the oxidative phosphorylation rate in osteosarcoma cells grown under normoxic conditions
The main findings of the present study are: first, IF1 does not affect the mitochondrial volume nor the level of dimeric F1F0ATPase in human osteosarcoma cells; second, IF1-silenced cells have a reproducibly higher ⌬m associated with a lower respiration rate than parental cells; and third, IF1 has a higher affinity for the dimeric form of ATP synthase than the monomeric form
Summary
The role of the inhibitor factor, IF1, of the F1F0-ATPase complex has not been fully defined. Results: IF1-silenced osteosarcoma cancer cells show increased mitochondrial membrane potential (⌬m) and decreased ADPinduced respiration rate. We showed that IF1-silenced cells proliferate normally, consume glucose, and release lactate as controls do, and contain a normal steady-state ATP level. IF1-silenced cells displayed an enhanced steady-state mitochondrial membrane potential and consistently showed a reduced ADP-stimulated respiration rate. In the parental cells (i.e. control cells containing IF1) the inhibitor protein was found to be associated with the dimeric form of the ATP synthase complex, we propose that the interaction of IF1 with the complex either directly, by increasing the catalytic activity of the enzyme, or indirectly, by improving the structure of mitochondrial cristae, can increase the oxidative phosphorylation rate in osteosarcoma cells grown under normoxic conditions
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