α-Ketoglutarate dehydrogenase: A mitochondrial redox sensor

Aaron L. McLain, Pamela A. Szweda, Luke I. Szweda

Research output: Contribution to journalReview article

78 Scopus citations

Abstract

α-Ketoglutarate dehydrogenase (KGDH), a key regulatory enzyme within the Krebs cycle, is sensitive to mitochondrial redox status. Treatment of mitochondria with H 2O 2 results in reversible inhibition of KGDH due to glutathionylation of the cofactor, lipoic acid. Upon consumption of H 2O 2, glutathione is removed by glutaredoxin restoring KGDH activity. Glutathionylation appears to be enzymatically catalysed or require a unique microenvironment. This may represent an antioxidant response, diminishing the flow of electrons to the respiratory chain and protecting sulphydryl residues from oxidative damage. KGDH is, however, also susceptible to oxidative damage. 4-Hydroxy-2-nonenal (HNE), a lipid peroxidation product, reacts with lipoic acid resulting in enzyme inactivation. Evidence indicates that HNE modified lipoic acid is cleaved from KGDH, potentially the first step of a repair process. KGDH is therefore a likely redox sensor, reversibly altering metabolism to reduce oxidative damage and, under severe oxidative stress, acting as a sentinel of mitochondrial viability.

Original languageEnglish (US)
Pages (from-to)29-36
Number of pages8
JournalFree Radical Research
Volume45
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • free radicals
  • glutathionylation
  • mitochondria
  • redox signalling
  • α -Ketoglutarate dehydrogenase

ASJC Scopus subject areas

  • Biochemistry

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