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

J 2020

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

SMOLKOVA, Katarina; Jitka SPACKOVA; Klara GOTVALDOVA; Ales DVORAK; Alena KRENKOVA et al.

Základní údaje

Originální název

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

Autoři

SMOLKOVA, Katarina; Jitka SPACKOVA; Klara GOTVALDOVA; Ales DVORAK; Alena KRENKOVA; Martin HUBALEK; Blanka HOLENDOVA; Libor VITEK a Petr JEZEK

Vydání

Nature Scientific Reports, BERLIN, NATURE PORTFOLIO, 2020, 2045-2322

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30300 3.3 Health sciences

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.380

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:90127/20:00139238

Organizační jednotka

CIISB II

Klíčová slova anglicky

PROTEIN ACETYLATION; CARBOXYLATIONDEACETYLATESMECHANISMSGROWTHCOA2-HYDROXYGLUTARATEHYPERACETYLATIONMETABOLISMDYNAMICSvvvvv

Štítky

ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 29. 3. 2025 14:53, Mgr. Eva Dubská

Anotace

V originále

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.

Návaznosti

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

SMOLKOVA, Katarina; Jitka SPACKOVA; Klara GOTVALDOVA; Ales DVORAK; Alena KRENKOVA; Martin HUBALEK; Blanka HOLENDOVA; Libor VITEK a Petr JEZEK. SIRT3 and GCN5L regulation of NADP plus - and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2. Nature Scientific Reports. BERLIN: NATURE PORTFOLIO, 2020, roč. 10, č. 1, s. 1-12. ISSN 2045-2322. Dostupné z: https://doi.org/10.1038/s41598-020-65351-z.

@article{2487420,
   author = {Smolkova, Katarina and Spackova, Jitka and Gotvaldova, Klara and Dvorak, Ales and Krenkova, Alena and Hubalek, Martin and Holendova, Blanka and Vitek, Libor and Jezek, Petr},
   article_location = {BERLIN},
   article_number = {1},
   doi = {https://doi.org/10.1038/s41598-020-65351-z},
   keywords = {PROTEIN ACETYLATION; CARBOXYLATIONDEACETYLATESMECHANISMSGROWTHCOA2-HYDROXYGLUTARATEHYPERACETYLATIONMETABOLISMDYNAMICSvvvvv},
   language = {eng},
   issn = {2045-2322},
   journal = {Nature Scientific Reports},
   title = {SIRT3 and GCN5L regulation of NADP plus - and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2},
   url = {https://www.nature.com/articles/s41598-020-65351-z},
   volume = {10},
   year = {2020}
}

TY  - JOUR
ID  - 2487420
AU  - Smolkova, Katarina - Spackova, Jitka - Gotvaldova, Klara - Dvorak, Ales - Krenkova, Alena - Hubalek, Martin - Holendova, Blanka - Vitek, Libor - Jezek, Petr
PY  - 2020
TI  - SIRT3 and GCN5L regulation of NADP plus - and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2
JF  - Nature Scientific Reports
VL  - 10
IS  - 1
SP  - 1-12
EP  - 1-12
PB  - NATURE PORTFOLIO
SN  - 20452322
KW  - PROTEIN ACETYLATION
KW  - CARBOXYLATIONDEACETYLATESMECHANISMSGROWTHCOA2-HYDROXYGLUTARATEHYPERACETYLATIONMETABOLISMDYNAMICSvvvvv
UR  - https://www.nature.com/articles/s41598-020-65351-z
N2  - 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.
ER  -

SMOLKOVA, Katarina; Jitka SPACKOVA; Klara GOTVALDOVA; Ales DVORAK; Alena KRENKOVA; Martin HUBALEK; Blanka HOLENDOVA; Libor VITEK a Petr JEZEK. SIRT3 and GCN5L regulation of NADP plus - and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2. \textit{Nature Scientific Reports}. BERLIN: NATURE PORTFOLIO, 2020, roč.~10, č.~1, s.~1-12. ISSN~2045-2322. Dostupné z: https://doi.org/10.1038/s41598-020-65351-z.

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