Exp Mol Med.
2017 Feb;49(2):e291. 10.1038/emm.2016.157.
Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes
- Affiliations
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- 1Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea. qsang@yonsei.ac.kr
- 2Mitohormesis Translational Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
- 3Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
- 4Mitochondrial Function, Nestlé Institute of Health Sciences, Lausanne, Switzerland.
- 5Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
- KMID: 2375021
- DOI: http://doi.org/10.1038/emm.2016.157
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 Ca²âº homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca²âº release and thereby deplete ER Ca²âº stores. The resulting ER Ca²âº 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 Ca²âº release, cytosolic and mitochondrial matrix Ca²âº concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca²âº depletion mediate persistent Ca²âº influx, further impairing cytosolic and mitochondrial Ca²âº homeostasis. Mitochondrial Ca²âº 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.
MeSH Terms
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Adenosine Triphosphate
Apoptosis
Calcium*
Cytosol
Diabetes Complications
Endoplasmic Reticulum
Fatty Acids, Nonesterified
Homeostasis
Insulin Resistance
Ion Channels
Metabolic Diseases
Metabolism
Oxidative Stress*
Protein Folding
Reactive Oxygen Species
Superoxides
Adenosine Triphosphate
Calcium
Fatty Acids, Nonesterified
Ion Channels
Reactive Oxygen Species
Superoxides
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