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Branched Chain Keto-Acids Exert Biphasic Effects on α-Ketoglutarate-Stimulated Respiration in Intact Rat Liver Mitochondria

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Abstract

Pathophysiological concentrations of branched chain keto-acids (BCKAs), such as those that occur in maple syrup urine disease, inhibit oxygen consumption in liver homogenates and brain slices and the enzymatic activity of α-ketoglutarate- and pyruvate dehydrogenase complexes. Consistent with previous work, studies in isolated rat liver mitochondria indicate that three BCKAs, α-ketoisocaproate (KIC), α-keto-β-methylvalerate (KMV) and α-ketoisovalerate (KIV), preferentially inhibited State 3 respiration supported by α-ketoglutarate relative to succinate or glutamate/malate (KIC, >100-fold; KMV, >10-fold; KIV, >4-fold). KIC was also the most potent inhibitor (Ki,app 13 ± 2 μM). Surprisingly, sub-inhibitory concentrations of KIC and KMV can markedly stimulate State 3 respiration of mitochondria utilizing α-ketoglutarate and glutamate/malate, but not succinate. The data suggest that physiological concentrations of the BCKAs may modulate mitochondrial respiration.

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Abbreviations

BCKAs:

Branched chain keto acids

KMV:

DL-α-keto-β-methyl-n-valeric acid

KIV:

α-ketoisovaleric acid

KIC:

α-ketoisocaproic acid

α-KGDHC:

α-ketoglutarate dehydrogenase complex

PDHC:

Pyruvate dehydrogenase complex

MSUD:

Maple syrup urine disease

V ATP4 :

State 4 respiration

V3 :

State 3 respiration

Vapp :

Apparent Vmax

Km,app :

Apparent Km

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Acknowledgments

We thank the many individuals who have commented on various aspects of this work, which was supported by P-01 AG14390 (Director: JP Blass, Key Investigator Subproject 2, Kristal).

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Author notes

  1. Alexander I. Shestopalov

    Present address: Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119899, Russia

Authors and Affiliations

  1. Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY, 10605, USA

    Alexander I. Shestopalov & Bruce S. Kristal

  2. Departments of Biochemistry and Neuroscience, Weill Medical College of Cornell University, 1300 York Ave., New York, NY, 10021, USA

    Bruce S. Kristal

Authors
  1. Alexander I. Shestopalov
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  2. Bruce S. Kristal
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Correspondence to Bruce S. Kristal.

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Special issue dedicated to John P. Blass.

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Shestopalov, A.I., Kristal, B.S. Branched Chain Keto-Acids Exert Biphasic Effects on α-Ketoglutarate-Stimulated Respiration in Intact Rat Liver Mitochondria. Neurochem Res 32, 947–951 (2007). https://doi.org/10.1007/s11064-007-9291-3

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  • DOI: https://doi.org/10.1007/s11064-007-9291-3

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