Počet záznamů: 1  

SIRT3 and GCN5L regulation of NADP plus - and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2

  1. 1.
    0531053 - FGÚ 2021 RIV GB eng J - Článek v odborném periodiku
    Smolková, Katarína - Špačková, Jitka - Gotvaldová, Klára - Dvořák, Aleš - Křenková, Alena - Hubálek, Martin - Holendová, Blanka - Vítek, L. - Ježek, Petr
    SIRT3 and GCN5L regulation of NADP plus - and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2.
    Scientific Reports. Roč. 10, č. 1 (2020), č. článku 8677. ISSN 2045-2322. E-ISSN 2045-2322
    Grant CEP: GA ČR(CZ) GA17-01813S; GA ČR(CZ) GA20-00408S
    Výzkumná infrastruktura: CIISB - 90043
    Institucionální podpora: RVO:67985823 ; RVO:61388963
    Klíčová slova: IDH2 * SIRT3 * 2-hydroxyglutarate * 2HG * GCN5L * mitochondria * acetylation
    Obor OECD: Biochemistry and molecular biology; Analytical chemistry (UOCHB-X)
    Impakt faktor: 4.380, rok: 2020
    Způsob publikování: Open access
    https://doi.org/10.1038/s41598-020-65351-z

    Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.
    Trvalý link: http://hdl.handle.net/11104/0309806

     
     
Počet záznamů: 1  

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