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α-Ketoglutarate inhibits autophagy
Elisa Elena Baracco1,2, Francesca Castoldi1,2, Sylvère Durand1,2
1Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Descartes, Université Paris Diderot, "Metabolism, Cancer and Immunity", Paris 75006, France.
Aging
|June 8, 2019
Summary
Dimethyl α-ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG), and octyl α-ketoglutarate (O-KG) esters deliver α-ketoglutarate intracellularly. While all increase α-ketoglutarate, they uniquely impact metabolites and autophagy.
Area of Science:
- Cellular metabolism
- Autophagy regulation
- Biochemistry
Background:
- α-ketoglutarate (AKG) is a crucial metabolite for cellular functions.
- AKG is membrane-impermeable and requires ester forms for cell entry.
- Ester derivatives like DMKG, TFMKG, and O-KG are used to increase intracellular AKG.
Purpose of the Study:
- To systematically compare the metabolic and functional effects of three AKG ester prodrugs: DMKG, TFMKG, and O-KG.
- To investigate the impact of these esters on intracellular metabolite profiles and autophagy.
- To determine the specific effects of each ester on cellular processes like oxidative phosphorylation and toxicity.
Main Methods:
- Mass spectrometric metabolomics was employed to analyze metabolite changes.
- Cells were cultured under nutrient-free and complete medium conditions.
- Autophagy induction and inhibition were assessed.
- Oxidative phosphorylation and cellular toxicity were measured.
Main Results:
- All three esters (DMKG, TFMKG, O-KG) effectively increased intracellular α-ketoglutarate levels.
- Each ester induced unique, non-shared changes in other cellular metabolites.
- All esters reduced starvation-induced autophagy; TFMKG and O-KG increased baseline autophagy.
- O-KG inhibited oxidative phosphorylation and caused cellular toxicity, unlike DMKG and TFMKG.
Conclusions:
- Intracellular α-ketoglutarate appears to inhibit autophagy triggered by nutrient deprivation.
- The tested AKG esters exhibit distinct off-target effects on cellular metabolism and autophagy.
- O-KG demonstrates specific inhibitory effects on oxidative phosphorylation and cellular toxicity.
- The choice of AKG ester prodrug can significantly influence experimental outcomes beyond AKG delivery.
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