Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent L-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

Normalizing hif-1α signaling improves cellular glucose metabolism and blocks the pathological pathways of hyperglycemic damage / Iacobini, C.; Vitale, M.; Pugliese, G.; Menini, S.. - In: BIOMEDICINES. - ISSN 2227-9059. - 9:9(2021), pp. 1-19. [10.3390/biomedicines9091139]

Normalizing hif-1α signaling improves cellular glucose metabolism and blocks the pathological pathways of hyperglycemic damage

Iacobini C.
Co-primo
;
Vitale M.
Co-primo
;
Pugliese G.;Menini S.
Ultimo
2021

Abstract

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent L-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.
2021
carnosine; cellular energetics; diabetes; glycolysis; hyperglycemia; inflammation; methylglyoxal; prolyl 4-hydroxylase 2; trans-resveratrol; warburg effect
01 Pubblicazione su rivista::01a Articolo in rivista
Normalizing hif-1α signaling improves cellular glucose metabolism and blocks the pathological pathways of hyperglycemic damage / Iacobini, C.; Vitale, M.; Pugliese, G.; Menini, S.. - In: BIOMEDICINES. - ISSN 2227-9059. - 9:9(2021), pp. 1-19. [10.3390/biomedicines9091139]
File allegati a questo prodotto
File Dimensione Formato  
Iacobini_Normalizing_2021.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 2.75 MB
Formato Adobe PDF
2.75 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1572120
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 12
social impact