Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes

Mackenzie, Ruth M.; Salt, Ian P.; Miller, William H.; Logan, Angela; Ibrahim, Hagar; Degasperi, Andrea; Dymott, Jane A.; Hamilton, Carlene A.; Murphy, Michael P.; Delles, Christian; Dominiczak, Anna F.

doi:10.1042/cs20120239

Cited by 62 publications

(50 citation statements)

References 41 publications

(71 reference statements)

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“…AMPK can be induced by glucose deprivation and mitochondrial O 2 − production (Wu and Wei, 2012) (Mackenzie et al, 2013) to reduce total ROS via the promotion of pentose phosphate shunt-mediated NADPH production (Jeon et al, 2012). Consistent with these studies, Hif-1α −/− MEFs that stably expressed HIGD1A increased pAMPK levels to a greater extent than control cells during glucose deprivation (Fig.…”

Section: Resultsmentioning

confidence: 99%

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

Ameri¹,

Jahangiri²,

Rajah³

et al. 2015

Cell Reports

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Hypoxia-Inducible Gene Domain Family Member 1A (HIGD1A) is a survival factor induced by Hypoxia-inducible Factor-1 (HIF1). HIF1 regulates many responses to oxygen deprivation but viable cells within hypoxic perinecrotic solid tumor regions frequently lack HIF1α. HIGD1A is induced in these HIF-deficient extreme environments and interacts with the mitochondrial electron transport chain to repress oxygen consumption, enhance AMPK activity and lower cellular ROS levels. Importantly, HIGD1A decreases tumor growth but promotes tumor cell survival in vivo. The human Higd1a gene is located on chromosome 3p22.1, where many tumor suppressor genes reside. Consistent with this, the Higd1a gene promoter is differentially methylated in human cancers, preventing its hypoxic induction. When hypoxic tumor cells are confronted with glucose deprivation, however, DNA methyltransferase activity is inhibited, enabling HIGD1A expression, metabolic adaptation and possible dormancy induction. Our findings therefore reveal important new roles for this family of mitochondrial proteins in cancer biology.

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Section: Resultsmentioning

confidence: 99%

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

Ameri¹,

Jahangiri²,

Rajah³

et al. 2015

Cell Reports

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“…Mitochondrial hormesis was initially used to describe the beneficial acute increase in mitochondrial respiration when cells are exposed to toxins such as heavy metals (94). A beneficial role of mitochondrial superoxide may be linked to improved endothelial function because 2-DOG was found to stimulate AMPK and phosphorylate eNOS via stimulation of ROS (95). Exercise has been shown to stimulate muscle ROS production, and a study in humans found that exercise increased adiponectin levels and insulin sensitivity; however, pretreatment with antioxidants (vitamin C and vitamin E) led to a loss of the protective benefits of exercise (96).…”

Section: New Theory Of Mitochondrial Hormesis As a Central Player In mentioning

confidence: 99%

Mitochondrial Hormesis and Diabetic Complications

2015

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The concept that excess superoxide production from mitochondria is the driving, initial cellular response underlying diabetes complications has been held for the past decade. However, results of antioxidant-based trials have been largely negative. In the present review, the data supporting mitochondrial superoxide as a driving force for diabetic kidney, nerve, heart, and retinal complications are reexamined, and a new concept for diabetes complications—mitochondrial hormesis—is presented. In this view, production of mitochondrial superoxide can be an indicator of healthy mitochondria and physiologic oxidative phosphorylation. Recent data suggest that in response to excess glucose exposure or nutrient stress, there is a reduction of mitochondrial superoxide, oxidative phosphorylation, and mitochondrial ATP generation in several target tissues of diabetes complications. Persistent reduction of mitochondrial oxidative phosphorylation complex activity is associated with the release of oxidants from nonmitochondrial sources and release of proinflammatory and profibrotic cytokines, and a manifestation of organ dysfunction. Restoration of mitochondrial function and superoxide production via activation of AMPK has now been associated with improvement in markers of renal, cardiovascular, and neuronal dysfunction with diabetes. With this Perspective, approaches that stimulate AMPK and PGC1α via exercise, caloric restriction, and medications result in stimulation of mitochondrial oxidative phosphorylation activity, restore physiologic mitochondrial superoxide production, and promote organ healing.

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“…Kukidome and co-workers have demonstrated that metformin could prevent diabetes complications by multiple mechanisms, for instance, decreasing blood glucose level, reducing ROS production through AMPK activation and/or PGC-1␣ induction and promotes mitochondrial biogenesis in HUVEC cells [150]. It has also been shown that ROS enhances AMPK activation in the endothelium of patients with coronary artery disease and diabetes [151]. This finding may implicate high glucose levels in the induction of endothelial dysfunction by increasing ROS production, which in turn leads to the activation of AMPK [144].…”

Section: Er Stress and Pathogenesis Of Diabetes Complicationsmentioning

confidence: 97%