Related Experiment Videos
The effect of malate on propionate mitochondrial toxicity
T Matsuishi1, D A Stumpf, K Chrislip
1Division of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60611.
Abstract:
Propionic acidemia occasionally produces a toxic encephalopathy resembling Reye's syndrome, indicating disruption of mitochondrial metabolism. Liver mitochondria respiratory control ratios were reduced 46% by 5 mM propionate; inhibition correlated with matrix propionyl-CoA levels. L-Malate prevented the toxic effect of propionate and reduced the propionyl-CoA matrix concentration by 62%. The beneficial effect of L-malate is apparently due to stimulation of succinate efflux because the effect is blocked by benzylmalonate, an inhibitor of the dicarboxylate carrier. Matrix concentration of label from [1-14C]propionate was not affected by L-malate and/or benzylmalonate. L-Malate may be useful in the treatment of patients with propionic acidemia.
Insights
Propionic acidemia disrupts mitochondrial metabolism, causing toxic encephalopathy. L-malate may treat this by reducing toxic propionyl-CoA levels in liver mitochondria.
Area of Science:
- Biochemistry
- Mitochondrial Metabolism
- Inborn Errors of Metabolism
Background:
- Propionic acidemia is a metabolic disorder that can lead to toxic encephalopathy, mimicking Reye's syndrome.
- This condition is characterized by the disruption of mitochondrial energy metabolism.
- Elevated propionyl-CoA in the mitochondrial matrix is a key factor in the observed toxicity.
Purpose of the Study:
- To investigate the protective effect of L-malate against propionate-induced mitochondrial dysfunction.
- To elucidate the mechanism by which L-malate exerts its beneficial effects in propionic acidemia.
- To explore the potential therapeutic role of L-malate in managing propionic acidemia.
Main Methods:
- Isolated liver mitochondria were treated with propionate and L-malate.
- Respiratory control ratios were measured to assess mitochondrial function.
- Mitochondrial propionyl-CoA levels were quantified, and the effect of benzylmalonate (a dicarboxylate carrier inhibitor) was evaluated.
Main Results:
- Propionate (5 mM) significantly inhibited liver mitochondria respiratory control ratios by 46%, correlating with increased matrix propionyl-CoA.
- L-malate prevented the toxic effects of propionate and reduced matrix propionyl-CoA by 62%.
- The protective effect of L-malate was abolished by benzylmalonate, suggesting involvement of the dicarboxylate carrier and succinate efflux.
Conclusions:
- L-malate demonstrates a protective effect against propionate-induced mitochondrial toxicity in vitro.
- The mechanism involves the stimulation of succinate efflux via the dicarboxylate carrier, reducing matrix propionyl-CoA.
- L-malate shows promise as a potential therapeutic agent for patients with propionic acidemia.