ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2013
The negative impact of α-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 60 citations in OpenAlex.
- Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain.Journal of bioenergetics and biomembranes · 2015Trial
- Pathological Interplay between Inflammation and Mitochondria Aggravates Glutamate Toxicity.International journal of molecular sciences · 2024Review
- Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia.Scientific reports · 2024Article
- Mitochondrial Alpha-Keto Acid Dehydrogenase Complexes: Recent Developments on Structure and Function in Health and Disease.Sub-cellular biochemistry · 2024Review
- Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.Redox biology · 2023Article
- Viability of HepG2 and MCF-7 cells is not correlated with mitochondrial bioenergetics.Scientific reports · 2023Article
- The α-Ketoglutarate Dehydrogenase Complex as a Hub of Plasticity in Neurodegeneration and Regeneration.International journal of molecular sciences · 2022Review
- Reverse and Forward Electron Flow-Induced HAntioxidants (Basel, Switzerland) · 2022Article
- Proline Oxidation Supports Mitochondrial ATP Production When Complex I Is Inhibited.International journal of molecular sciences · 2022Article
- Selective linkage of mitochondrial enzymes to intracellular calcium stores differs between human-induced pluripotent stem cells, neural stem cells, and neurons.Journal of neurochemistry · 2021Article
- Chemical individuality in T cells: A Garrodian view of immunometabolism.Immunological reviews · 2020Review
- Exclusive neuronal detection of KGDHC-specific subunits in the adult human brain cortex despite pancellular protein lysine succinylation.Brain structure & function · 2020Article
- The Effect of 2-Ketobutyrate on Mitochondrial Substrate-Level Phosphorylation.Neurochemical research · 2019Article
- The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease.Biochimica et biophysica acta. Molecular basis of disease · 2017Article
- The effect of respiration buffer composition on mitochondrial metabolism and function.PloS one · 2017Article
- Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations.The Biochemical journal · 2016Article
- Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells.Scientific reports · 2016Article
- Article
- Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions.Acta neuropathologica communications · 2015Article
- The RNA-binding protein HuR is essential for the B cell antibody response.Nature immunology · 2015Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
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.
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