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Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart
Published on: September 28, 2016
Coenzyme A sequestration in rat hearts oxidizing ketone bodies
1Department of Medicine, University of Texas Medical School, Houston 77030.
The Journal of Clinical Investigation
|March 1, 1992
Summary
Ketone bodies impair heart function by reducing available Coenzyme A (CoA), inhibiting key enzymes. Supplementing CoA precursors restores heart performance, suggesting CoA levels are critical for cardiac energy metabolism during ketone oxidation.
Area of Science:
- Biochemistry
- Cardiology
- Mitochondrial Physiology
Background:
- Ketone body oxidation can lead to heart contractile failure.
- This failure is hypothesized to result from inhibition of 2-oxoglutarate dehydrogenase by intramitochondrial Coenzyme A (CoA) sequestration.
- Acetoacetyl-CoA and acetyl-CoA formation during ketone metabolism are implicated in CoA sequestration.
Purpose of the Study:
- To investigate if acetoacetate oxidation decreases intramitochondrial CoA levels in rat heart mitochondria.
- To determine if increasing available CoA can improve contractile function in hearts oxidizing acetoacetate.
Main Methods:
- Oxidation of acetoacetate by isolated rat heart mitochondria.
- Measurement of intramitochondrial nonesterified CoA [CoASH] levels.
- Perfusion of isolated working rat hearts with CoA precursors or carnitine.
- Assessment of cardiac contractile performance and 2-oxoglutarate dehydrogenase activity.
Main Results:
- Acetoacetate oxidation by mitochondria decreased state 3 respiration and intramitochondrial [CoASH].
- Increasing tissue CoA content via precursors relieved 2-oxoglutarate dehydrogenase inhibition and improved heart function.
- Carnitine administration increased tissue CoA but did not enhance cardiac performance, suggesting distinct CoA pools.
Conclusions:
- Ketone body-induced inhibition of 2-oxoglutarate dehydrogenase is caused by reduced intramitochondrial CoASH.
- This citric acid cycle inhibition is a likely mechanism for cardiac contractile failure during ketone metabolism.
- Evidence suggests the existence of separate intramitochondrial CoA pools with differing functional roles.
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