Glutaredoxins concomitant with optimal ROS activate AMPK through S-glutathionylation to improve glucose metabolism in type 2 diabetes

Dong, Kelei; Wu, Meiling; Liu, Xiaomin; Huang, Yanjie; Zhang, Dongyang; Wang, Yiting; Yan, Liang-Jun; Shi, Dongyun

doi:10.1016/j.freeradbiomed.2016.10.007

Cited by 45 publications

(33 citation statements)

References 43 publications

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“…Although still speculative, it is possible that GRX1 mediates protein S-glutathionylation by first being S-glutathionylated itself allowing for transfer of glutathione to a protein target. Recent work has shown that GRX1 can be S-glutathionylated, indicating that this may account for how GRX1 can conjugate glutathione to cysteine (Dong et al, 2016). This can also be demonstrated with the cellular glutathione probe, GRX1-roGFP2, which changes fluorescence following its GSSG-mediated S-glutathionylation.…”

Section: Controlling Mitochondrial Ros Production By Redox Signalsmentioning

confidence: 87%

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Kuksal

Chalker

Mailloux

2017

Biological Chemistry

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Abstract:The molecular oxygen (O 2 ) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O 2 is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H 2 O 2 , are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H 2 O 2 elimination pathways are well characterized in mitochondria. However, less is known about how H 2 O 2 production is controlled. The present review examines the importance of mitochondrial H 2 O 2 in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H 2 O 2 can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H 2 O 2 production.

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Section: Controlling Mitochondrial Ros Production By Redox Signalsmentioning

confidence: 87%

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Kuksal

Chalker

Mailloux

2017

Biological Chemistry

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“…UA-induced AMPK activation may be also mediated by UA-associated oxidative and nitrosative stress (this study). It has been reported that reactive oxygen species and reactive nitrogen species may activate AMPK [54–56]. Nitric oxide may also activate ataxia telangiectasia mutated (ATM) kinase, DNA damage response kinase [57], that in turn activate AMPK and promote cytotoxic autophagy in MCF-7 cells [58].…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells

et al. 2017

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Plant-derived pentacyclic triterpenotids with multiple biological activities are considered as promising candidates for cancer therapy and prevention. However, their mechanisms of action are not fully understood. In the present study, we have analyzed the effects of low dose treatment (5–20 µM) of ursolic acid (UA) and betulinic acid (BA) on breast cancer cells of different receptor status, namely MCF-7 (ER+, PR+/−, HER2−), MDA-MB-231 (ER−, PR−, HER2−) and SK-BR-3 (ER−, PR−, HER2+). UA-mediated response was more potent than BA-mediated response. Triterpenotids (5–10 µM) caused G0/G1 cell cycle arrest, an increase in p21 levels and SA-beta-galactosidase staining that was accompanied by oxidative stress and DNA damage. UA (20 µM) also diminished AKT signaling that affected glycolysis as judged by decreased levels of HK2, PKM2, ATP and lactate. UA-induced energy stress activated AMPK that resulted in cytotoxic autophagy and apoptosis. UA-mediated elevation in nitric oxide levels and ATM activation may also account for AMPK activation-mediated cytotoxic response. Moreover, UA-promoted apoptosis was associated with decreased pERK1/2 signals and the depolarization of mitochondrial membrane potential. Taken together, we have shown for the first time that UA at low micromolar range may promote its anticancer action by targeting glycolysis in phenotypically distinct breast cancer cells.

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“…10,11 A study in rats showed that impairment of the mitochondrial respiratory chain results in mitochondrial ROS overproduction, which in turn causes oxidative damage to mitochondrial structure and function, leading to abnormal changes in intracellular signalling and the development of insulin resistance. 12,13 The regulation and maintenance of mitochondrial function require regulators, such as peroxisome proliferator-activated receptor-c coactivator-1a (PGC-1a) and mitofusin-2 (Mfn-2), which play critical roles in regulating mitochondria biogenesis, respiration and OXPHOS. 14 Besides, studies had shown that adipose PGC-1a deficiency clearly leaded to systemic deregulation of glucose homoeostasis, and obesity induced by a high-fat diet (HFD) reduced Mfn-2 expression in muscle.…”

mentioning

confidence: 99%

NEFA‐induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non‐alcoholic steatohepatitis

Gao

Lei

et al. 2018

J Cellular Molecular Medi

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The aim of this study was to investigate the changes in hepatic oxidative phosphorylation (OXPHOS) complexes (COs) in patients and cows with non‐alcoholic steatohepatitis (NASH) and to investigate the mechanism that links mitochondrial dysfunction and hepatic insulin resistance induced by non‐esterified fatty acids (NEFAs). Patients and cows with NASH displayed high blood NEFAs, TNF‐α and IL‐6 concentrations, mitochondrial dysfunction and insulin resistance. The protein levels of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), mitofusin‐2 (Mfn‐2) and OXPHOS complexes (human: COI and COIII; cow: COI‐IV) were significantly decreased in patients and cows with NASH. NEFA treatment significantly impaired mitochondrial function and, increased reactive oxygen species (ROS) production, and excessive ROS overactivated the JNK and p38MAPK pathways and induced insulin resistance in cow hepatocytes. PGC‐1α and Mfn‐2 overexpression significantly decreased the NEFA‐induced ROS production and TNF‐α and IL‐6 mRNA expressions, reversed the inhibitory effect of NEFAs on mitochondrial function and attenuated the overactivation of the ROS‐JNK/p38MAPK pathway, alleviated insulin resistance induced by NEFAs in cow hepatocytes and HepG2 cells. These findings indicate that NEFAs induce mitochondrial dysfunction and insulin resistance mediated by the ROS‐JNK/p38MAPK pathway. PGC‐1α or Mfn‐2 overexpression reversed the lipotoxicity of NEFAs on mitochondrial dysfunction and insulin resistance. Our study clarified the mechanism that links hepatic mitochondrial dysfunction and insulin resistance in NASH.

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Glutaredoxins concomitant with optimal ROS activate AMPK through S-glutathionylation to improve glucose metabolism in type 2 diabetes

Cited by 45 publications

References 43 publications

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells

NEFA‐induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non‐alcoholic steatohepatitis

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