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Propionate mitochondrial toxicity in liver and skeletal muscle: acyl CoA levels
T Matsuishi1, D A Stumpf, M Seliem
1Division of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60611.
Abstract:
Propionic acidemia occasionally produces a toxic encephalopathy resembling Reye syndrome, indicating disruption of mitochondrial metabolism. Understanding the mitochondrial effect of propionate might clarify the pathophysiology. Liver mitochondria are inhibited by propionate (5 mM) while muscle mitochondria are not. Preincubation is required to inhibit liver mitochondria, suggesting that propionate is metabolized to propionyl CoA. Liver and skeletal muscle mitochondria incubated with [1-14C]propionate contain similar quantities of matrix isotope and release comparable [14C]CO2. However, only liver mitochondria accumulated significant propionyl CoA, which was largely (68%) synthesized from propionate. Carnitine reduced the level of liver matrix propionyl CoA. Inhibition of respiratory control ratios by propionate correlated with propionyl CoA levels. These results support the hypothesis that acyl CoA esters are toxic and that carnitine exerts its protective effect by converting acyl CoA esters to acylcarnitine esters.
Insights
Propionic acidemia causes toxic encephalopathy by disrupting mitochondrial metabolism. Carnitine protects against this by converting toxic propionyl CoA to protective acylcarnitine esters.
Area of Science:
- Biochemistry
- Mitochondrial Biology
- Metabolic Disorders
Background:
- Propionic acidemia can lead to toxic encephalopathy, mimicking Reye syndrome.
- This suggests a disruption in mitochondrial metabolism is involved.
- Clarifying the mitochondrial effects of propionate is crucial for understanding the pathophysiology.
Purpose of the Study:
- To investigate the specific effects of propionate on liver and muscle mitochondria.
- To elucidate the mechanism by which propionate inhibits mitochondrial function.
- To determine the role of carnitine in mitigating propionate toxicity.
Main Methods:
- Incubation of isolated liver and muscle mitochondria with propionate and [1-14C]propionate.
- Measurement of propionyl CoA accumulation and [14C]CO2 release.
- Assessment of mitochondrial respiratory control ratios and the effect of carnitine.
Main Results:
- Liver mitochondria, but not muscle mitochondria, were inhibited by propionate after preincubation.
- Propionate was metabolized to propionyl CoA, which accumulated significantly in liver mitochondria.
- Carnitine administration reduced liver matrix propionyl CoA levels and protected respiratory control ratios.
Conclusions:
- Acyl CoA esters, specifically propionyl CoA, are toxic to mitochondria.
- Carnitine's protective effect in propionic acidemia involves the conversion of toxic acyl CoA esters to less harmful acylcarnitine esters.
- This highlights a potential therapeutic strategy for propionic acidemia-induced encephalopathy.