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Effect of oxalate on function of kidney mitochondria
T Strzelecki1, B R McGraw, C R Scheid
1University of Massachusetts Medical School, Worcester 01655.
Abstract:
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.
Insights
Oxalate exposure impairs kidney mitochondria function by affecting membrane integrity, not energy production. This interaction may be key in forming kidney stones.
Area of Science:
- Mitochondrial Physiology
- Nephrology
- Biochemistry
Background:
- Oxalate is transported into mitochondria via the dicarboxylate carrier.
- Previous studies suggest oxalate's role in kidney stone formation.
- Understanding oxalate's mitochondrial effects is crucial for nephrolithiasis research.
Purpose of the Study:
- To investigate the in vitro effects of oxalate on kidney mitochondria function.
- To determine if oxalate exposure causes mitochondrial dysfunction promoting kidney stone formation.
Main Methods:
- Isolated mitochondria from kidney and liver were used.
- Assays included malate and succinate oxidation, respiration with various substrates, and response to CCCP and Ca2+ ionophore A23187.
- Calcium uptake and efflux rates were measured.
Main Results:
- Oxalate competitively inhibited malate and succinate uptake/oxidation.
- Oxalate attenuated mitochondrial respiration increase induced by CCCP or Ca2+ ionophore, more significantly in kidney mitochondria.
- Oxalate inhibited calcium-induced mitochondrial swelling more effectively in kidney than liver mitochondria.
Conclusions:
- Oxalate interacts more with kidney than liver mitochondria, particularly affecting membrane integrity.
- Oxalate's impact on mitochondrial membrane permeability/integrity is more critical than its effects on energy production or calcium handling in calcium oxalate microlith formation.
- These findings highlight oxalate's specific detrimental effects on kidney mitochondria, contributing to kidney stone pathogenesis.