The effects of methylprednisolone on oxidative phosphorylation in Concanavalin-A-stimulated thymocytes. Top-down elasticity analysis and control analysis.
The glucocorticoid methylprednisolone has clinically important anti-inflammatory effects at high concentrations through unknown mechanisms. Methylprednisolone at 0.2 mg/10(7) cells inhibits respiration in Concanavalin-A(ConA)-stimulated thymocytes from rats by about 20%. We have used top-down elasticity analysis to identify the blocks of reactions within oxidative phosphorylation in thymocytes whose kinetics are significantly affected by treatment with methylprednisolone. At this concentration methylprednisolone greatly inhibited the reactions of substrate oxidation and increased mitochondrial proton leak but did not significantly affect the synthesis and and turnover of ATP by the phosphorylating system. Metabolic control analysis showed that oxygen consumption by ConA-treated thymocytes was controlled largely (0.51) by the phosphorylating system but also by proton leak (0.32) and substrate oxidation (0.17); this is similar to the distribution of control in hepatocytes, suggesting that this pattern may be general in cells. Methylprednisolone lowered control by the phosphorylating system to 0.26 and raised control by substrate oxidation to 0.37. From these results we conclude that the inhibition of respiration in ConA-stimulated thymocytes by methylprednisolone at this concentration results from an inhibition of substrate oxidation and a smaller stimulation of mitochondrial proton leak, with only a minor contribution of any effects within the phosphorylating system.
Buttgereit
F
F
Medizinische Klinik, Humboldt-Universität (Charité), Berlin, Germany.
Grant
A
A
Müller
M
M
Brand
M D
MD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology*; D005260:Female; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008775:Methylprednisolone / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects
D003208:Concanavalin A; D000255:Adenosine Triphosphate; D008775:Methylprednisolone