Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders

European Journal of Nutrition, Apr 2016

Purpose The severity of untreated or refractory diabetes mellitus has been functionally linked to elevated concentrations of free plasma glucose, clinically defined as hyperglycemia. Operationally, the pathophysiological presentations of prolonged hyperglycemia may be categorized within insulin-dependent and insulin-independent, type 1 and type 2 diabetic phenotypes, respectively. Accordingly, major areas of empirical biomedical research have focused on the elucidation of underlying mechanisms driving key cellular signaling systems that are significantly altered in patients presenting with diabetes-associated chronic hyperglycemia. Methods Presently, we provide a translationally oriented review of key studies evaluating the aberrant effects of hyperglycemia on two major signaling pathways linked to debilitating cellular and systemic effects via targeted disruption of mitochondrial bioenergetics: (1) advanced glycation end-products (AGEs)/and their cognate receptor for advanced glycation end-products (RAGEs), and (2) the hexosamine biosynthetic pathway (HBP). Results In preclinical models, cultured vascular endothelial cells exposed to hyperglycemic glucose concentrations were observed to produce enhanced levels of reactive oxygen species (ROS) functionally linked to increased formation of AGEs and expression of their cognate RAGEs. Importantly, inhibitors of AGEs formation, mitochondrial complex II, or un-couplers of oxidative phosphorylation, were observed to significantly reduce the effects of hyperglycemia on ROS production and cellular damage, thereby establishing a critical linkage to multiple levels of mitochondrial functioning. Hyperglycemia-mediated enhancement of mitochondrial ROS/superoxide production in vascular endothelial cells has been functionally linked to the shunting of glucose into the HBP with resultant long-term activation of pro-inflammatory signaling processes. Additionally, exposure of cultured cells to hyperglycemic conditions resulted in enhanced HBP-mediated inhibition of protein subunits of mitochondrial respiratory complexes I, III, and IV, intimately associated with normative cellular bioenergetics and ATP production. Conclusions Convergent lines of evidence link chronic hyperglycemic conditions to aberrant expression of AGEs/RAGEs and HBP signaling pathways in relation to the pathophysiological formation of ROS and pro-inflammatory processes on the functional dysregulation of mitochondrial bioenergetics.

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Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders

Hyperglycemia‑associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders George B. Stefano 0 Sean Challenger 0 Richard M. Kream 0 0 MitoGenetics LLC , 3 Bioscience Park Drive, Suite 307, Farmingdale, NY 11735 , USA 1 George B. Stefano Purpose The severity of untreated or refractory diabetes mellitus has been functionally linked to elevated concentrations of free plasma glucose, clinically defined as hyperglycemia. Operationally, the pathophysiological presentations of prolonged hyperglycemia may be categorized within insulin-dependent and insulin-independent, type 1 and type 2 diabetic phenotypes, respectively. Accordingly, major areas of empirical biomedical research have focused on the elucidation of underlying mechanisms driving key cellular signaling systems that are significantly altered in patients presenting with diabetes-associated chronic hyperglycemia. Methods Presently, we provide a translationally oriented review of key studies evaluating the aberrant effects of hyperglycemia on two major signaling pathways linked to debilitating cellular and systemic effects via targeted disruption of mitochondrial bioenergetics: (1) advanced glycation end-products (AGEs)/and their cognate receptor for advanced glycation end-products (RAGEs), and (2) the hexosamine biosynthetic pathway (HBP). Results In preclinical models, cultured vascular endothelial cells exposed to hyperglycemic glucose concentrations were observed to produce enhanced levels of reactive oxygen species (ROS) functionally linked to increased formation of AGEs and expression of their cognate RAGEs. Importantly, inhibitors of AGEs formation, mitochondrial complex II, or un-couplers of oxidative phosphorylation, were observed to significantly reduce the effects of hyperglycemia on ROS production and cellular damage, thereby Mitochondria; Glucose; Hyperglycemia; Diabetes; ATP; Aerobic glycolysis; Advanced glycation end-products; Receptor for advanced glycation endproducts; Hexosamine biosynthetic pathway; Hexosamine biosynthetic pathway - establishing a critical linkage to multiple levels of mitochondrial functioning. Hyperglycemia-mediated enhancement of mitochondrial ROS/superoxide production in vascular endothelial cells has been functionally linked to the shunting of glucose into the HBP with resultant long-term activation of pro-inflammatory signaling processes. Additionally, exposure of cultured cells to hyperglycemic conditions resulted in enhanced HBP-mediated inhibition of protein subunits of mitochondrial respiratory complexes I, III, and IV, intimately associated with normative cellular bioenergetics and ATP production. Conclusions Convergent lines of evidence link chronic hyperglycemic conditions to aberrant expression of AGEs/ RAGEs and HBP signaling pathways in relation to the pathophysiological formation of ROS and pro-inflammatory processes on the functional dysregulation of mitochondrial bioenergetics. Introduction The severity of untreated or refractory diabetes mellitus has been functionally linked to elevated concentrations of free plasma glucose, clinically defined as hyperglycemia. The pathophysiological presentations of prolonged hyperglycemia may be operationally characterized within insulin-dependent and insulin-independent, type 1 and type 2, diabetic phenotypes, respectively. Accordingly, a relatively broad spectrum of long-term hyperglycemia-associated cellular and metabolic insults has observed in diverse peripheral organ systems and central nervous tissues [ 1 ]. Mechanistically, the biomedical literature has focused on the elucidation of key cellular signaling systems that are significantly altered in patients presenting with diabetesassociated chronic hyperglycemia. For example, in both type 1 and type 2 diabetic patients, macro- and microvascular complications may arise from prolonged exposure to high glucose levels via the intracellular formation of advanced glycation end-products (AGEs), which enhance coordinate expression of the cognate receptor for advanced glycation end-products (RAGE) [ 2 ]. Chronic hyperglycemia has been functionally linked to aberrant signaling processes mediated by selective enzymes of the hexosamine biosynthetic pathway (HBP), thereby promoting posttranslational modification of key cellular regulatory enzymes and membrane proteins [ 3 ]. Additional hypotheses have emerged on the underlying mechanisms of hyperglycemicinduced diabetic complications, including altered expression and signaling by protein kinase C isoforms [ 4 ] and increased flux through the aldose reductase pathway [ 5 ]. An overriding or unifying mechanism of diabetic pathophysiology may involve hyperglycemia-driven mitochondrial tricarboxylic acid (TCA) cycle dysregulation leading to respiratory complex III dysfunction and the production of high levels of reactive oxygen species (ROS) in the form of superoxide [ 6 ]. Presently, we coordinate (...truncated)


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George B. Stefano, Sean Challenger, Richard M. Kream. Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders, European Journal of Nutrition, 2016, pp. 2339-2345, Volume 55, Issue 8, DOI: 10.1007/s00394-016-1212-2