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Difference between revisions of "Kiss 2012 Abstract Bioblast"

From Bioblast
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|abstract=The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation
|abstract=The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation


Objectives: provision of succinyl-CoA by the alpha-ketoglutarate dehydrogenase complex (KGDHC) is essential for generation of matrix ATP (or GTP) by substrate-level phosphorylation catalyzed by succinyl-CoA ligase. A decline in KGDHC activity has been associated with neurodegeneration.
== Objectives: == provision of succinyl-CoA by the alpha-ketoglutarate dehydrogenase complex (KGDHC) is essential for generation of matrix ATP (or GTP) by substrate-level phosphorylation catalyzed by succinyl-CoA ligase. A decline in KGDHC activity has been associated with neurodegeneration.


Methods: mitochondrial phosphorylation was investigated in tissues of transgenic mice with deficiencies in KGDHC subunits.
Methods: mitochondrial phosphorylation was investigated in tissues of transgenic mice with deficiencies in KGDHC subunits.

Revision as of 11:48, 30 October 2012

Kiss G (2012) ..... Mitochondr Physiol Network 17.12.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Gergely Kiss(1), Csaba Konrad(1), Judit Doczi(1), Anatoly A. Starkov(2), Hibiki Kawamata(2), Giovanni Manfredi(2), Steven F. Zhang(2), Gary E. Gibson(3), M Flint Beal(2), Vera Adam-Vizi(1) and Christos Chinopoulos(1, 2) (2012)

Event: Bioblast 2012

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

== Objectives: == provision of succinyl-CoA by the alpha-ketoglutarate dehydrogenase complex (KGDHC) is essential for generation of matrix ATP (or GTP) by substrate-level phosphorylation catalyzed by succinyl-CoA ligase. A decline in KGDHC activity has been associated with neurodegeneration.

Methods: mitochondrial phosphorylation was investigated in tissues of transgenic mice with deficiencies in KGDHC subunits.

Results: 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) exhibiting a 20-48% decrease in KGDHC activity. Import of ATP into the matrix of mitochondria from transgenic mice was attributed to a shift in the reversal potential of the adenine nucleotide translocase towards more negative values due to diminished matrix substrate-level phosphorylation, causing 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 further corroborated 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.

Conclusions: we propose that KGDHC-associated pathologies are subserved by the inability of respiration-impaired mitochondria to rely on β€œin-house” mitochondrial ATP reserves.


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Affiliations and author contributions

(1) Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary

(2) Weill Medical College Cornell University, New York, NY, 10021, USA

(3) Weill Cornell Medical College/Burke Medical Research Institute, White Plains, NY, 10605, USA

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