Mimicking caloric restriction for anti-aging effects: The pro-oxidant role of alpha-ketoglutarate

Bayliak, Maria M.; Gospodaryov, Dmytro V.; Lushchak, Volodymyr I.

doi:10.1016/j.cotox.2022.02.012

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…Namely, Wu et al 60 demonstrated that αKG induces autophagy and apoptosis upon induction of ROS and inhibition of mTOR in renal cell carcinoma cell lines, 786O and ACHN, in a dose-dependent manner. Moreover, the levels of ROS induced by different doses of exogenous αKG were involved in either prolonging (moderate induction of ROS) or shortening (high induction of ROS) the lifespans of different model organisms 61 . The dose-dependent effects of ROS on apoptosis/necrosis turning point 62 , could also explain why 200 mM αKG induced predominantly necrosis of PBMCs, whereas 100 mM induced both apoptosis and necrosis.…”

Section: Discussionmentioning

confidence: 99%

Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response

Milanović,

Bekić,

Đokić

et al. 2024

Int. J. Biol. Sci.

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Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1β secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs' capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.

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Section: Discussionmentioning

confidence: 99%