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

Kiss, G [Kiss, Gergely (biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Konrad, C [Konrád, Csaba (biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Doczi, J [Dóczi, Judit (biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Starkov, AA; Kawamata, H; Manfredi, G; Zhang, SF; Gibson, GE; Beal, MF; Adam-Vizi, V [Ádám, Veronika (biokémia), szerző] Orvosi Biokémiai Intézet (SE / AOK / I); Chinopoulos, C [Chinopoulos, Christos (Bioenergetika), szerző] Orvosi Biokémiai Intézet (SE / AOK / I)

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: FASEB JOURNAL 0892-6638 1530-6860 27 (6) pp. 2392-2406 2013
  • SJR Scopus - Biochemistry: D1
Azonosítók
Szakterületek:
    A decline in alpha-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 approximately 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.-Kiss, G., Konrad, C., Doczi, J., Starkov, A. A., Kawamata, H., Manfredi, G., Zhang, S. F., Gibson, G. E., Beal, M. F., Adam-Vizi, V., Chinopoulos, C. The negative impact of alpha-ketoglutarate dehydrogenase complex deficiency on matrix substrate-level phosphorylation.
    Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
    2021-05-10 03:56