Selective Inactivation of α-Ketoglutarate Dehydrogenase and Pyruvate Dehydrogenase: Reaction of Lipoic Acid with 4-Hydroxy-2-nonenal

Previous research has established that 4-hydroxy-2-nonenal, a highly toxic product of lipid peroxidation, is a potent inhibitor of mitochondrial respiration

Kenneth M. Humphries; Luke I. Szweda

2002

Scholarcy highlights

  • Previous research has established that 4-hydroxy-2-nonenal, a highly toxic product of lipid peroxidation, is a potent inhibitor of mitochondrial respiration
  • Because of the central role of ketoglutarate dehydrogenase in metabolism and emerging evidence that free radicals contribute to mitochondrial dysfunction associated with numerous diseases, it is of great interest to further characterize the mechanism of inhibition
  • Treatment of rat heart mitochondria with HNE resulted in the selective inhibition of KGDH and pyruvate dehydrogenase, while other NADH-linked dehydrogenases and electron chain complexes were unaffected
  • To determine the mechanism of inhibition, the effects of HNE on purified KGDH and PDH were examined. These studies revealed that inactivation by HNE was greatly enhanced in the presence of substrates that reduce the sulfur atoms of lipoic acid covalently bound to the E2 subunits of KGDH and PDH
  • Use of anti-lipoic acid antibodies indicated that HNE modified lipoic acid in both purified enzyme preparations and mitochondria and that this modification was dependent upon the presence of substrates
  • These results identify a potential mechanism whereby free radical production and subsequent lipid peroxidation lead to specific modification of ketoglutarate dehydrogenase and pyruvate dehydrogenase and inhibition of NADH-linked mitochondrial respiration

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