Mitigation of glucolipotoxicity-induced apoptosis, mitochondrial dysfunction, and metabolic stress by n-acetyl cysteine in pancreatic β-cells

Arwa Alnahdi, Annie John, Haider Raza

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Glucolipotoxicity caused by hyperglycemia and hyperlipidemia are the common features of diabetes-induced complications. Metabolic adaptation, particularly in energy metabolism; mitochondrial dysfunction; and increased inflammatory and oxidative stress responses are considered to be the main characteristics of diabetes and metabolic syndrome. However, due to various fluctuating endogenous and exogenous stimuli, the precise role of these factors under in vivo conditions is not clearly understood. In the present study, we used pancreatic β-cells, Rin-5F, to elucidate the molecular and metabolic changes in glucolipotoxicity. Cells treated with high glucose (25 mM) and high palmitic acid (up to 0.3 mM) for 24 h exhibited increased caspase/poly-ADP ribose polymerase (PARP)-dependent apoptosis followed by DNA fragmentation, alterations in mitochondrial membrane permeability, and bioenergetics, accompanied by alterations in glycolytic and mitochondrial energy metabolism. Our results also demonstrated alterations in the expression of mammalian target of rapamycin (mTOR)/5 adenosine monophosphate-activated protein kinase (AMPK)-dependent apoptotic and autophagy markers. Furthermore, pre-treatment of cells with 10 mM N-acetyl cysteine attenuated the deleterious effects of high glucose and high palmitic acid with improved cellular functions and survival. These results suggest that the presence of high energy metabolites enhance mitochondrial dysfunction and apoptosis by suppressing autophagy and adapting energy metabolism, mediated, at least in part, via enhanced oxidative DNA damage and mTOR/AMPK-dependent cell signaling.

Original languageEnglish
Article number239
JournalBiomolecules
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2020

Keywords

  • Apoptosis
  • Autophagy
  • Glucolipotoxicity
  • Mitochondrial dysfunction
  • Palmitic acid
  • Rin-5F cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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