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The effects of oxalate on kidney mitochondria were evaluated in vitro to test whether oxalate exposure leads to derangement(s) in mitochondrial function that could in turn promote the formation of kidney stones. Our previous studies demonstrated that oxalate is transported across the mitochondrial membrane via the dicarboxylate carrier. The present studies indicated that oxalate competitively inhibits the uptake and oxidation of exogenous malate and succinate in isolated mitochondria but has no effect on mitochondrial respiration in the presence of a mixture of glutamate plus malate or glutamate plus pyruvate. Oxalate attenuates the increase in mitochondrial respiration produced by the uncoupler CCCP or by the Ca2+ ionophore A23187, and the latter effect is more pronounced in kidney than in liver mitochondria. The apparent Ki of oxalate for the response to Ca2+ ionophore is 1.9 +/- 0.3 mM in kidney and 6.1 +/- 0.2 mM in liver mitochondria. Similarly, the ability of oxalate to attenuate calcium-induced swelling of mitochondria is more dramatic in kidney than in liver mitochondria (apparent KiS of 1.7 +/- 0.1 and 18.2 +/- 0.7 mM, respectively). Oxalate has no effect on the rate of calcium uptake by energized mitochondria or on the rate of ruthenium red-insensitive calcium efflux from mitochondria in either tissue. The above findings indicate that oxalate interacts with the inner mitochondrial membrane or with processes controlling membrane integrity to a greater extent in kidney than liver mitochondria. The effects of oxalate on membrane permeability or integrity may be more important than its effects on mitochondrial energy production or calcium sequestration in the pathogenesis of calcium oxalate microlith formation in the kidney.

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Intraperitoneal administration of maleate produced an increase in blood alpha-ketoacid, acetoacetate, and free fatty acids. The effect of this treatment on blood glucose levels depended on whether the rats were fed or fasted. In fed rats it was accompanied by slight, transient hyperglycemia connected with depletion of liver glycogen stores. In fasted animals moderate hypoglycemia was observed. The in vivo conversion of various precursors into blood glucose was not inhibited, suggesting that maleate does not affect hepatic gluconeogenesis. Neither was a direct effect on liver glycogenolysis observed. On the other hand, maleate inhibited renal gluconeogenesis from various substrates and stimulated anerobic glycolysis in kidney cortical alices. The data are interpreted in terms of increased utilization and decreased production of glucose by the kidney followed by secondary changes in liver carbohydrate metabolism.

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This study was performed to evaluate whether cyclosporine penetrates kidney mitochondria and impairs mitochondrial functions, causing nephrotoxicity. Exposure of rat kidney cortical mitochondria in vitro to cyclosporine had little effect on the oxidation of glutamate plus malate. Oxidation of succinate was markedly inhibited by a toxic level of cyclosporine (25 to 50 nmol/mg protein) under resting (State 4) and ADP-stimulated (State 3) conditions. Under uncoupling conditions, induced by the proton ionophore, CCCP or by the calcium ionophore, A23187 plus calcium, mitochondrial respiration was unchanged by cyclosporine. In mitochondria isolated from rats treated with an immunosuppressive dose of cyclosporine (25 mg/kg/day, p.o.), respiration was not significantly impaired. The respiration stimulated by ADP was only diminished in mitochondria from rats treated with 75 mg/kg. The rate of calcium uptake was unchanged by cyclosporine under in vitro and in vivo conditions. Kidney mitochondria of untreated rats maintained in a medium containing respiratory substrates and phosphate released spontaneously accumulated calcium that was accompanied by large amplitude swelling and enhanced respiration. Cyclosporine in vitro inhibited the process of spontaneous calcium discharge at the concentration range of 0.1 to 0.5 nmol/mg protein. Swelling and respiration induced by accumulated calcium was significantly diminished in kidney mitochondria isolated from cyclosporine-treated rats given doses of 25 or 75 mg/kg. The data obtained indicate that cyclosporine interacts with the membrane of kidney mitochondria in virtually the same way under in vitro and in vivo conditions. Cyclosporine at an immunosuppressive level impairs calcium-induced membrane permeability and at a toxic level, the rate of ADP phosphorylation.

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