Difference between revisions of "Kiss 2013 FASEB J"
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{{Publication | {{Publication | ||
|title=Kiss G, Konrad C, Doczi J, Starkov AA, Kawamata H, Manfredi G, Zhang SF, Gibson GE, Beal MF, Adam-Vizi V, Chinopoulos C (2013) The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation. FASEB J [ | |title=Kiss G, Konrad C, Doczi J, Starkov AA, Kawamata H, Manfredi G, Zhang SF, Gibson GE, Beal MF, Adam-Vizi V, Chinopoulos C (2013) The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation. FASEB J 27:2392-406. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/23475850 PMID: 23475850 Open Access] | |||
|authors=Kiss G, Konrad C, Doczi J, Starkov AA, Kawamata H, Manfredi G, Zhang SF, Gibson GE, Beal MF, Adam-Vizi V, Chinopoulos C | |authors=Kiss G, Konrad C, Doczi J, Starkov AA, Kawamata H, Manfredi G, Zhang SF, Gibson GE, Beal MF, Adam-Vizi V, Chinopoulos C | ||
|year=2013 | |year=2013 | ||
|journal=FASEB J | |journal=FASEB J | ||
|mipnetlab=HU Budapest Chinopoulos C | |abstract=A decline in Ξ±-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 βΌ30% 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. | ||
|keywords=Adenine nucleotide translocase; Reversal potential; Succinyl-CoA ligase, F<sub>0</sub>βF<sub>1</sub> ATP synthase | |||
|mipnetlab=HU Budapest Chinopoulos C | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration, Genetic knockout;overexpression | |||
|organism=Mouse | |||
|tissues=Nervous system | |||
|enzymes=TCA cycle and matrix dehydrogenases | |||
|diseases=Neurodegenerative | |||
|topics=ADP, ATP, Ion;substrate transport | |||
|couplingstates=OXPHOS | |||
|pathways=N | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
}} | }} |
Revision as of 17:53, 7 November 2016
Kiss G, Konrad C, Doczi J, Starkov AA, Kawamata H, Manfredi G, Zhang SF, Gibson GE, Beal MF, Adam-Vizi V, Chinopoulos C (2013) The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation. FASEB J 27:2392-406. |
Kiss G, Konrad C, Doczi J, Starkov AA, Kawamata H, Manfredi G, Zhang SF, Gibson GE, Beal MF, Adam-Vizi V, Chinopoulos C (2013) FASEB J
Abstract: A decline in Ξ±-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 βΌ30% 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. β’ Keywords: Adenine nucleotide translocase; Reversal potential; Succinyl-CoA ligase, F0βF1 ATP synthase
β’ O2k-Network Lab: HU Budapest Chinopoulos C
Labels: MiParea: Respiration, Genetic knockout;overexpression
Pathology: Neurodegenerative
Organism: Mouse Tissue;cell: Nervous system
Enzyme: TCA cycle and matrix dehydrogenases Regulation: ADP, ATP, Ion;substrate transport Coupling state: OXPHOS Pathway: N HRR: Oxygraph-2k