Neurochemical Research

, Volume 32, Issue 4–5, pp 947–951

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

Original Paper


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.


Mitochondria Respiration α-Ketoglutarate dehydrogenase complex 



Branched chain keto acids


DL-α-keto-β-methyl-n-valeric acid


α-ketoisovaleric acid


α-ketoisocaproic acid


α-ketoglutarate dehydrogenase complex


Pyruvate dehydrogenase complex


Maple syrup urine disease


State 4 respiration


State 3 respiration


Apparent Vmax


Apparent Km


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Alexander I. Shestopalov
    • 1
    • 3
  • Bruce S. Kristal
    • 1
    • 2
  1. 1.Dementia Research ServiceBurke Medical Research InstituteWhite PlainsUSA
  2. 2.Departments of Biochemistry and NeuroscienceWeill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical BiologyMoscow State UniversityMoscowRussia

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