Improved efficiency of hepatic mitochondrial function in rats with cholestasis induced by an acute dose of alpha-naphthylisothiocyanate.
Cholestasis is a feature of many chronic human liver diseases. Previous studies pointed out an impairment of mitochondrial function as a cause of hepatocyte dysfunction leading to cholestatic liver injury. This study was aimed to evaluate liver mitochondrial bioenergetics of alpha-naphthylisothiocyanate-treated Wistar rats, an experimental model of cholestasis. Serum markers of liver injury and endogenous adenine nucleotides were measured. Changes in membrane potential, mitochondrial respiration, and alterations in mitochondrial permeability transition pore induction were monitored. In rats injected with alpha-naphthylisothiocyanate, liver injury with cholestasis developed within 48 h, as indicated by both serum enzyme activities and total bilirubin concentration. Liver mitochondria isolated from alpha-naphthylisothiocyanate-treated rats had a higher state 3 respiration, respiratory control ratio, ADP/O, and endogenous ATP/ADP ratio compared to controls. No change in state 4 respiration was observed. Associated with these parameters, cholestatic mitochondria exhibited an increased resistance to disruption of mitochondrial calcium homeostasis due to permeability transition pore induction. Hepatic mitochondria isolated from alpha-naphthylisothiocyanate-treated rats exhibited an improved efficiency. These data indicate that an adaptive response to resist cell death occurs during alpha-naphthylisothiocyanate-induced acute cholestasis.
Department of Zoology, Center for Neurosciences and Cell Biology of Coimbra, University of Coimbra, 3004-517, Coimbra, Portugal.
Anabela P
AP
Rolo
Paulo J
PJ
Oliveira
Raquel
R
Seiça
Maria S
MS
Santos
António J
AJ
Moreno
Carlos M
CM
Palmeira
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000503:physiopathology*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008933:Mitochondrial Swelling / Q000502:physiology; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D000227:Adenine Nucleotides; D009249:NADP; D015058:1-Naphthylisothiocyanate; D002950:Citrate (si)-Synthase; D002118:Calcium