Differences in 2-oxoglutarate dehydrogenase regulation in liver and kidney.
In response to acidosis, renal ammoniagenesis is stimulated, enhancing urinary buffering power, while hepatic ammoniagenesis and ureagenesis decrease, so as to spare bicarbonate consumed in the urea cycle. 2-Oxoglutarate (2-OG) levels can regulate ammoniagenesis in kidney and gluconeogenesis in liver and kidney. Since the activity of 2-oxoglutarate dehydrogenase (2-OGDH) has an important influence on cellular levels of 2-OG, this study evaluated the effects of pH on 2-OGDH in liver and kidney and found that: (1) the isolated enzyme from both organs has the same pH-sensitivity; (2) 2-OGDH flux measured in intact mitochondria was inhibited by increasing H+ in liver, but stimulated in kidney; (3) transport of 2-OG into the mitochondria was not rate-limiting; (4) liver mitochondrial 2-OGDH exhibited a strong preference for 2-OG generated within the mitochondria from glutamate-oxaloacetate transaminase (GOT), suggesting that channelling between GOT and 2-OGDH occurs. Since complexation between 2-OGDH and GOT occurs in vitro, we propose that the degree of complexation is higher in liver than in kidney, such that most of the 2-OGDH may be complexed to GOT in liver. In the liver the inherent H(+)-sensitivity of 2-OGDH is masked by the pH-sensitivity of GOT and the glutamate-aspartate carrier.
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
B C
BC
Smith
L A
LA
Clotfelter
J Y
JY
Cheung
K F
KF
LaNoue
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006863:Hydrogen-Ion Concentration; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000378:metabolism; D017830:Octoxynol; D009928:Organ Specificity; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003902:Detergents; D005971:Glutamates; D018698:Glutamic Acid; D011092:Polyethylene Glycols; D017830:Octoxynol; D007655:Ketoglutarate Dehydrogenase Complex; D002118:Calcium