Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes

Luong Dai Ly, Shanhua Xu, Seong Kyung Choi, Chae Myeong Ha, Themis Thoudam, Seung Kuy Cha, Andreas Wiederkehr, Claes B. Wollheim, In Kyu Lee, Kyu Sang Park

Research output: Contribution to journalReview article

70 Citations (Scopus)

Abstract

Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications.

Original languageEnglish
Article numbere291
JournalExperimental and Molecular Medicine
Volume49
Issue number2
DOIs
Publication statusPublished - 2017 Feb 3

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Ly, L. D., Xu, S., Choi, S. K., Ha, C. M., Thoudam, T., Cha, S. K., Wiederkehr, A., Wollheim, C. B., Lee, I. K., & Park, K. S. (2017). Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes. Experimental and Molecular Medicine, 49(2), [e291]. https://doi.org/10.1038/emm.2016.143