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Difference between revisions of "Kiss 2012 Abstract Bioblast"

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(1) Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
(1) Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
(2) Weill Medical College Cornell University, New York, NY, 10021, USA
(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
(3) Weill Cornell Medical College/Burke Medical Research Institute, White Plains, NY, 10605, USA



Revision as of 11:46, 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 โ€œin-houseโ€ 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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