The negative impact of α-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation

Gergely Kiss, Csaba Konrad, Judit Doczi, Anatoly A. Starkov, Hibiki Kawamata, Giovanni Manfredi, Steven F. Zhang, Gary E. Gibson, M. Flint Beal, Vera Adam-Vizi, Christos Chinopoulos

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35 Citations (Scopus)


A decline in α-ketoglutarate dehydrogenase complex (KGDHC) activity has been associated with neurodegeneration. Provision of succinyl-CoA by KGDHC is essential for generation of matrix ATP (or GTP) by substrate-level phosphorylation catalyzed by succinyl- CoA ligase. Here, we demonstrate ATP consumption in respiration-impaired isolated and in situ neuronal somal mitochondria from transgenic mice with a deficiency of either dihydrolipoyl succinyltransferase (DLST) or dihydrolipoyl dehydrogenase (DLD) that exhibit a 20-48% decrease in KGDHC activity. Import of ATP into the mitochondrial matrix of transgenic mice was attributed to a shift in the reversal potential of the adenine nucleotide translocase toward more negative values due to diminished matrix substrate-level phosphorylation, which causes the translocase to reverse prematurely. Immunoreactivity of all three subunits of succinyl-CoA ligase and maximal enzymatic activity were unaffected in transgenic mice as compared to wild-type littermates. Therefore, decreased matrix substrate-level phosphorylation was due to diminished provision of succinyl-CoA. These results were corroborated further by the finding that mitochondria from wild-type mice respiring on substrates supporting substrate-level phosphorylation exhibited ~30% higher ADP-ATP exchange rates compared to those obtained from DLST +/- or DLD+/- littermates. We propose that KGDHC-associated pathologies are a consequence of the inability of respiration-impaired mitochondria to rely on "in-house" mitochondrial ATP reserves.

Original languageEnglish
Pages (from-to)2393-2406
Number of pages14
JournalFASEB Journal
Issue number6
Publication statusPublished - Jun 1 2013



  • Adenine nucleotide translocase
  • F-F ATP synthase
  • Reversal potential
  • Succinyl-CoA ligase

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Kiss, G., Konrad, C., Doczi, J., Starkov, A. A., Kawamata, H., Manfredi, G., Zhang, S. F., Gibson, G. E., Beal, M. F., Adam-Vizi, V., & Chinopoulos, C. (2013). The negative impact of α-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation. FASEB Journal, 27(6), 2393-2406.