Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes.
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.
Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea.|Mitohormesis Translational Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Luong Dai
LD
Ly
Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea.|Mitohormesis Translational Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Shanhua
S
Xu
Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea.
Seong-Kyung
SK
Choi
Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
Chae-Myeong
CM
Ha
Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
Themis
T
Thoudam
Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea.|Mitohormesis Translational Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Seung-Kuy
SK
Cha
Mitochondrial Function, Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Andreas
A
Wiederkehr
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Claes B
CB
Wollheim
Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
In-Kyu
IK
Lee
Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea.|Mitohormesis Translational Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Kyu-Sang
KS
Park
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010169:Palmitic Acids / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D018955:CD36 Antigens; D005230:Fatty Acids, Nonesterified; D010169:Palmitic Acids; D017382:Reactive Oxygen Species; D002118:Calcium