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Activating Autophagy by Aerobic Exercise in Mice
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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.

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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.

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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.