The negative impact of α-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation. Academic Article uri icon

Overview

MeSH

  • Animals
  • Female
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation
  • Substrate Specificity

MeSH Major

  • Acyltransferases
  • Amino Acid Metabolism, Inborn Errors
  • Dihydrolipoamide Dehydrogenase
  • Ketoglutarate Dehydrogenase Complex

abstract

  • 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.

publication date

  • June 2013

has subject area

  • Acyltransferases
  • Amino Acid Metabolism, Inborn Errors
  • Animals
  • Dihydrolipoamide Dehydrogenase
  • Female
  • Ketoglutarate Dehydrogenase Complex
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation
  • Substrate Specificity

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3659355

Digital Object Identifier (DOI)

  • 10.1096/fj.12-220202

PubMed ID

  • 23475850

Additional Document Info

start page

  • 2392

end page

  • 2406

volume

  • 27

number

  • 6