Organ-specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat.
To evaluate organ-specific metabolic changes after in vivo cyclosporine (CyA) treatment, male Wistar rats were treated with 10 mg/kg per day CyA orally for 6 days. Blood, kidney, liver, and heart tissues were extracted and analyzed by magnetic resonance spectroscopy (MRS). CyA decreased the energy balance [adenosine triphosphate (ATP)/adenosine diphosphate (ADP)] in all organs (kidney [control]: 50%, liver: 64%, and heart: 62%, all P<0.01) due to decreased activity of the mitochondrial Krebs cycle and oxidative phosphorylation. As a compensatory effect, anaerobic glycolysis (lactate) was increased. This was reflected in the low glucose level in the kidney and heart, but not in the liver where a significant decrease in glycogen was seen. Only in the kidney was mitochondrial inhibition accompanied by decreased polyunsaturated fatty acid (PUFA) concentrations and elevated lipid peroxidation. The metabolic marker for nephrotoxicity, trimethylamine-N-oxide (TMAO), was elevated. While CyA decreased mitochondrial homeostasis in all organ systems, cellular adaptation was different and most efficient in the liver.
Serkova
Natalie
N
Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Klawitter
Jost
J
Niemann
Claus U
CU
D000818:Animals; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D016572:Cyclosporine