Oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress

Diabetes mellitus is a chronic complex metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Hyperglycemia is only the most obvious biochemical marker of diabetes, and the main contributor to the development of diabetes complications is the cumulative effect of chronic hyperglycemia. Increasing evidence suggests that oxidative stress may be the key mediators of the deleterious effects of hyperglycemia. Mitochondria play a central role in the generation of reactive oxygen species and cell apoptosis. A number of conditions including nutrient excess that interfere with proper endoplasmic reticulum (ER) function may lead accumulation of unfolded proteins, which then trigger apoptotic as well as adaptive downstream signaling pathways. Many studies have also provided ample evidences that mitochondrial dysfunction and ER stress are most important pathogenic causes for the development of diabetes and its complications. Regulation mechanisms of how mitochondria play in the metabolism of glucose and fatty acids, the primary fuels used by cells to produce ATP, have been the subject of tremendous interests. Nonetheless, much remains to be investigated such as tissue-specific fuel selection and its relation with the pathogenesis of diabetes and complications. Cellular homeostasis depends upon the functional relationship between mitochondria and the ER. Propagation of calcium signaling from ER to mitochondria is involved in both ATP production and cell death. On the other hand, the ER requires ATP to function properly, which may make it the best site for sensing metabolic stress. In this article, oxidative stress, mitochondrial dysfunction and ER stress, especially their realtime interaction in diabetes and complication development will be reviewed.