title: Mitochondrial bioenergetic profile and responses to metabolic inhibition in human hepatocarcinoma cell lines with distinct differentiation characteristics.
abstract: The classical view of tumour cell bioenergetics has been recently revised. Then, the definition of the mitochondrial profile is considered of fundamental importance for the development of anti-cancer therapies, but it still needs to be clarified. We investigated two human hepatocellular carcinoma cell lines: the partially differentiated HepG2 and the undifferentiated JHH-6. High resolution respirometry revealed a marked impairment/uncoupling of OXPHOS in JHH-6 compared with HepG2, with the phosphorylation system limiting the capacity for electron transport much more in JHH-6. Blocking glycolysis or mitochondrial ATP synthase we demonstrated that in JHH-6 ATP synthase functions in reverse and consumes glycolytic ATP, thereby sustaining ΔΨm. A higher expression level of ATP synthase Inhibitor Factor 1 (IF1), a higher extent of IF1 bound to ATP synthase and a lower ATPase/synthase capacity were documented in JHH-6. Thus, here IF1 appears to down-regulate the reverse mode of ATPsynthase activity, thereby playing a crucial role in controlling energy waste and ΔΨm. These results, while confirming the over-expression of IF1 in cancer cells, are the first to indicate an inverse link between cell differentiation status and IF1 (expression level and regulatory function).
authors: Department of Medical and Biological Sciences, MATI Centre of Excellence University of Udine, p.le Kolbe4, 33100 Udine, Italy.
authors: Rossana
authors: R
authors: Domenis
authors: Marina
authors: M
authors: Comelli
authors: Elena
authors: E
authors: Bisetto
authors: Irene
authors: I
authors: Mavelli
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D004579:Electron Transport / Q000235:genetics; D006019:Glycolysis; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010085:Oxidative Phosphorylation
chemical_list: D009363:Neoplasm Proteins; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases