Mitochondrial Reactive Oxygen Species and Type 1 Diabetes

Chen, Jing; Stimpson, Scott E.; Fernandez-Bueno, Gabriel A.; Mathews, Clayton E.

doi:10.1089/ars.2017.7346

Cited by 81 publications

(76 citation statements)

References 105 publications

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“…Alternatively, hydroxylation of the alpha subunit of HIF1α is inhibited by increased succinate/fumarate levels that occur when flux through the tricarboxylic acid (TCA) cycle slows, referred to as pseudohypoxia [30]. Mitochondrial dysfunction is an early manifestation of autoimmunity directed at beta cells and, therefore, the most likely inducer of activation of HIF1α signalling in type 1 diabetes [31]. The decreased density and perinuclear distribution of mitochondria noted in beta cells in type 1 diabetes in the current study resembles that observed as a defensive adaptation to stress accomplished by metabolic remodelling to high glycolysis and decreased oxidative phosphorylation [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

et al. 2019

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Aims/hypothesis The conserved hypoxia inducible factor 1 α (HIF1α) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1α signalling pathway. Methods RNA sequencing (RNA-Seq) data from human islets with type 1 diabetes or after cytokine exposure in vitro was evaluated for activation of HIF1α targets. This was corroborated by immunostaining human pancreases from individuals with type 1 diabetes for 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the key effector of HIF1α-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes. Results HIF1α signalling is activated (p = 4.5 × 10 −9) in islets from individuals with type 1 diabetes, and in human islets exposed in vitro to cytokines implicated in type 1 diabetes (p = 1.1 × 10 −14). Expression of PFKFB3 is increased fivefold (p < 0.01) in beta cells in type 1 diabetes and in human and rat islets exposed to cytokines that induced increased lactate production. HIF1α attenuates cytokine-induced cell death in beta cells. Conclusions/interpretation The conserved pro-survival HIF1α-mediated injury-response signalling is activated in beta cells in type 1 diabetes and likely contributes to the relatively slow rate of beta cell loss at the expense of early defective glucose-induced insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

et al. 2019

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“…In HG conditions and/or fatty acid oxidation, therefore, ROS overproduction causes cellular dysfunction, apoptosis, and inflammation in several insulin targets including the pancreas, liver, kidney, nerves, and vasculature [17,18].…”

Section: Pathophysiology Of Diabetes-related Metabolic Disorders Andmentioning

confidence: 99%

“…For instance, in T1DM, the generated ROS under metabolic or autoimmune stress in the cells of the pancreatic microenvironment may enhance damage of pancreatic β-cells, thereby reducing insulin secretion [17]. Regarding T2DM, HG-induced ROS production is considered a major contributor to damage and disease progression.…”

Section: Pathophysiology Of Diabetes-related Metabolic Disorders Andmentioning

confidence: 99%

Impact of Astaxanthin on Diabetes Pathogenesis and Chronic Complications

et al. 2020

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Oxidative stress (OS) plays a pivotal role in diabetes mellitus (DM) onset, progression, and chronic complications. Hyperglycemia-induced reactive oxygen species (ROS) have been shown to reduce insulin secretion from pancreatic β-cells, to impair insulin sensitivity and signaling in insulin-responsive tissues, and to alter endothelial cells function in both type 1 and type 2 DM. As a powerful antioxidant without side effects, astaxanthin (ASX), a xanthophyll carotenoid, has been suggested to contribute to the prevention and treatment of DM-associated pathologies. ASX reduces inflammation, OS, and apoptosis by regulating different OS pathways though the exact mechanism remains elusive. Based on several studies conducted on type 1 and type 2 DM animal models, orally or parenterally administrated ASX improves insulin resistance and insulin secretion; reduces hyperglycemia; and exerts protective effects against retinopathy, nephropathy, and neuropathy. However, more experimental support is needed to define conditions for its use. Moreover, its efficacy in diabetic patients is poorly explored. In the present review, we aimed to identify the up-to-date biological effects and underlying mechanisms of ASX on the ROS-induced DM-associated metabolic disorders and subsequent complications. The development of an in-depth research to better understand the biological mechanisms involved and to identify the most effective ASX dosage and route of administration is deemed necessary.

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“…Recent work demonstrating mitochondrial metabolic defects linked to inflammatory responses in immune cells of T1D donors may suggest an unexplored role for CLEC16A-mediated mitophagy in T1D(7,56). Likewise, defective mitophagy has been associated with elevated secretion of cytokines by macrophages(57,58).…”

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confidence: 99%

Mitophagy protects beta cells from inflammatory damage in diabetes

Sidarala

Pearson

Parekh

et al. 2020

Preprint

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Inflammatory damage contributes to β-cell failure in type 1 and 2 diabetes (T1D and T2D).Mitochondria are damaged by inflammatory signaling in β-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β-cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β-cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β-cell apoptosis. Thus, mitophagy promotes β-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent βcell failure in diabetes and may be beneficial in other inflammatory conditions.

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Mitochondrial Reactive Oxygen Species and Type 1 Diabetes

Abstract: Mechanistic studies are needed to investigate the mitochondrial pathways involved in autoimmunity, including T1D. These studies should seek to identify the role of mitochondria in regulating innate and adaptive immune cell activity and beta cell failure.

Cited by 81 publications

References 105 publications

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Impact of Astaxanthin on Diabetes Pathogenesis and Chronic Complications

Mitophagy protects beta cells from inflammatory damage in diabetes

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