Control analysis of mitochondrial metabolism in intact hepatocytes: effect of interleukin-1beta and interleukin-6.
Interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are produced by hepatic nonparenchymal cells after systemic injury and have been reported to inhibit ATP synthesis in hepatocytes, which may contribute to hepatic dysfunction in inflammatory states. To elucidate the mechanisms of action of IL-1beta and IL-6 on hepatocellular ATP synthesis, we measured the oxygen uptake rate (OUR) and mitochondrial membrane potential (MMP) of stable hepatocyte cultures, and analyzed the dynamic MMP response following the addition of mitochondrial inhibitors (antimycin A and oligomycin) with a model of mitochondrial metabolism. IL-1beta reduced mitochondrial OUR coupled to ATP synthesis via inhibition of phosphorylation reactions which dissipate the MMP, including ATP synthesis and consumption. Furthermore, the ATP synthesis rate in cytokine-free and IL-1beta-treated hepatocytes was controlled primarily by phosphorylation reactions, which corresponds to a state where the ATP synthesis rate closely follows the cellular energy demand. Thus, IL-1beta-mediated effects on electron transport and substrate oxidation reactions are not likely to significantly impact on ATP synthesis. IL-6 did not reduce mitochondrial OUR coupled to ATP synthesis, but shifted the control for ATP synthesis towards processes which generate the MMP, indicating that IL-6 induces a metabolic state where cellular functions are limited by the mitochondrial energy supply.
Berthiaume
François
F
Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
MacDonald
Annette D
AD
Kang
Yoon H
YH
Yarmush
Martin L
ML
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009840:Oligomycins / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D007375:Interleukin-1; D015850:Interleukin-6; D009840:Oligomycins; D000968:Antimycin A; D000255:Adenosine Triphosphate; D010100:Oxygen