Cyclosporine A: impact on mitochondrial function in endothelial cells.
BACKGROUND
Although cyclosporine A (CSA) is considered to be an efficient immunosuppressive compound in transplantation, vascular side effects like arterial hypertension, neurologic complications and other adverse reactions occur. Interference of CSA with mitochondrial function may be responsible for these side effects.


METHODS
We evaluated the effect of CSA on mitochondrial and glycolytic function by measuring fatty acid oxidation (FAO), activities of respiratory chain complexes (RC) and citratesynthase (CS), lactate/pyruvate-ratios, energy-rich phosphates as well as activities of some glycolytic enzymes in human umbilical vein endothelial cells.


RESULTS
After 48 h of CSA incubation, global FAO, RC-complexes 1 + 3; 4 and 5 as well as CS were compromised while energy charges were not reduced. Lactate/pyruvate-ratios increased; cellular lactate dehydrogenase (LDH)-, hexokinase- and phosphofructokinase-activities were not impaired by CSA. Moderate cellular toxicity, assessed by LDH leakage, appeared only at the highest CSA concentration.


CONCLUSIONS
Part of CSA toxicity may arise from alterations in mitochondrial function as judged by impaired FAO and respiratory chain enzymes. To some extent, energy balance seems to be maintained by cytosolic energy production. Although only demonstrated for endothelial cells, it is conceivable that such effects will alter energy metabolism of different organs with high oxidative energy demands.
Illsinger
Sabine
S
Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Janzen
Nils
N
Lücke
Thomas
T
Bednarczyk
Jolanthe
J
Schmidt
Karl-Heinz
KH
Hoy
Ludwig
L
Sander
Johannes
J
Das
Anibh M
AM
D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004579:Electron Transport; D004734:Energy Metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006019:Glycolysis; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation
D005227:Fatty Acids; D007166:Immunosuppressive Agents; D016572:Cyclosporine