scholarly journals IGF-1 Signalling Regulates Mitochondria Dynamics and Turnover through a Conserved GSK-3β–Nrf2–BNIP3 Pathway

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 147 ◽  
Author(s):  
Sarah Riis ◽  
Joss B. Murray ◽  
Rosemary O’Connor
Keyword(s):  
Mitochondrial Biogenesis ◽  
Glycogen Synthase ◽  
Mitochondrial Dynamics ◽  
Hypoxia Inducible Factor ◽  
Protective Role ◽  
Null Mouse ◽  
Related Factor ◽  
Mitochondrial Stress ◽  
Cellular Capacity ◽  
Gsk 3Β

The Insulin-like Growth Factor I (IGF-1) signalling pathway is essential for cell growth and facilitates tumourogenic processes. We recently reported that IGF-1 induces a transcriptional programme for mitochondrial biogenesis, while also inducing expression of the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), suggesting that IGF-1 has a key mitochondria-protective role in cancer cells. Here, we investigated this further and delineated the signaling pathway for BNIP3 induction. We established that IGF-1 induced BNIP3 expression through a known AKT serine/threonine kinase 1 (AKT)-mediated inhibitory phosphorylation on Glycogen Synthase Kinase-3β (GSK-3β), leading to activation of Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2/Nrf2) and acting through the downstream transcriptional regulators Nuclear Respiratory Factor-1 (NRF1) and Hypoxia-inducible Factor 1 subunit α (HIF-1α). Suppression of IGF-1 signaling, Nrf2 or BNIP3 caused the accumulation of elongated mitochondria and altered the mitochondrial dynamics. IGF-1R null Mouse Embryonic Fibroblasts (MEFs) were impaired in the BNIP3 expression and in the capacity to mount a cell survival response in response to serum deprivation or mitochondrial stress. IGF-1 signalling enhanced the cellular capacity to induce autophagosomal turnover in response to activation of either general autophagy or mitophagy. Overall, we conclude that IGF-1 mediated a mitochondria-protective signal that was coordinated through the cytoprotective transcription factor Nrf2. This pathway coupled mitochondrial biogenesis with BNIP3 induction, and increased the cellular capacity for autophagosome turnover, whilst enhancing survival under conditions of metabolic or mitochondrial stress.

Postnatal shifts in ischemic tolerance and cell survival signaling in murine myocardium

2013 ◽  
Vol 305 (10) ◽  
pp. R1171-R1181 ◽  
Author(s):  
Norman Y. Liaw ◽  
Louise See Hoe ◽  
Freya L. Sheeran ◽  
Jason N. Peart ◽  
John P. Headrick ◽  
...  
Keyword(s):  
Cell Survival ◽  
Connexin 43 ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
High Expression ◽  
Hsp27 Phosphorylation ◽  
Myocardial Stress ◽  
Survival Signaling ◽  
Gsk 3Β

The immature heart is known to be resistant to ischemia-reperfusion (I/R) injury; however, key proteins engaged in phospho-dependent signaling pathways crucial to cell survival are not yet defined. Our goal was to determine the postnatal changes in myocardial tolerance to I/R, including baseline expression of key proteins governing I/R tolerance and their phosphorylation during I/R. Hearts from male C57Bl/6 mice (neonates, 2, 4, 8, and 12 wk of age, n = 6/group) were assayed for survival signaling/effectors [Akt, p38MAPK, glycogen synthase kinase-3β (GSK-3β), heat shock protein 27 (HSP27), connexin-43, hypoxia-inducible factor-1α (HIF-1α), and caveolin-3] and regulators of apoptosis (Bax and Bcl-2) and autophagy (LC3B, Parkin, and Beclin1). The effect of I/R on ventricular function was measured in isolated perfused hearts from immature (4 wk) and adult (12 wk) mice. The neonatal myocardium exhibits a large pool of inactive Akt; high phospho-activation of p38MAPK, HSP27 and connexin-43; phospho-inhibition of GSK-3β; and high expression of caveolin-3, HIF-1α, LC3B, Beclin1, Bax, and Bcl-2. Immature hearts sustained less dysfunction and infarction following I/R than adults. Emergence of I/R intolerance in adult vs. immature hearts was associated with complex proteomic changes: decreased expression of Akt, Bax, and Bcl-2; increased GSK-3β, connexin-43, HIF-1α, LC3B, and Bax:Bcl-2; enhanced postischemic HIF-1α, caveolin-3, Bax, and Bcl-2; and greater postischemic GSK-3β and HSP27 phosphorylation. Neonatal myocardial stress resistance reflects high expression of prosurvival and autophagy proteins and apoptotic regulators. Notably, there is high phosphorylation of GSK-3β, p38MAPK, and HSP27 and low phosphorylation of Akt (high Akt “reserve”). Subsequent maturation-related reductions in I/R tolerance are associated with reductions in Akt, Bcl-2, LC3B, and Beclin1, despite increased expression and reduced phospho-inhibition of GSK-3β.

Zeaxanthin Attenuates the Vicious Circle Between Endoplasmic Reticulum Stress and Tau Phosphorylation: Involvement of GSK-3β Activation

2022 ◽  
pp. 1-14
Author(s):  
Li-Na Zhang ◽  
Meng-Jie Li ◽  
Ying-Hui Shang ◽  
Yun-Ru Liu ◽  
Huang Han-Chang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Fruits And Vegetables ◽  
Cell Injury ◽  
Glycogen Synthase ◽  
Tau Phosphorylation ◽  
Protective Role ◽  
Vicious Circle ◽  
Diphenyltetrazolium Bromide ◽  
Gsk 3Β

Background: Alzheimer’s disease (AD) characterized by neurofibrillary tangles caused by hyperphosphorylated tau is the most common cause of dementia. Zeaxanthin (Zea), derived from fruits and vegetables, may reduce the risk of AD. Endoplasmic reticulum stress (ERS) might cause memory impairment in AD. Objective: Here, we studied protective role of Zea on the relationship among ERS, activity of glycogen synthase kinase 3β (GSK-3β, tau phosphorylated kinase), and p-Tau (Ser 396 and Thr 231). Methods: The results were obtained in non-RA and RA group by using different treatment, such as 9-cis-retinoic acid (RA), TM (ERS inducer), Zea, 4-PBA (ERS inhibitor), and SB216763 (GSK-3β inhibitor). The methods included flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] for the detections of cell cycle and cell viability and western blot as a third measure of proteins in relation to ERS and tau phosphorylation. We have collected and analyzed all the data that suggested application of drugs for the treatment in non-RA and RA group. Results: Zea displays its protection on TM-induced cell injury, upregulation of GRP78 expression, and change of GSK-3β activity and tau phosphorylation when 4-PBA and SB216763 interfere with the process. Conclusion: These studies indicated that Zea is in vicious circle in ERS, GSK-3β, and tau phosphorylation, and further reflect its potential value in AD.

scholarly journals Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1α and Mediates Its Destabilization in a VHL-Independent Manner

2007 ◽  
Vol 27 (9) ◽  
pp. 3253-3265 ◽  
Author(s):  
Daniela Flügel ◽  
Agnes Görlach ◽  
Carine Michiels ◽  
Thomas Kietzmann
Keyword(s):  
Protein Kinase ◽  
Metabolic Diseases ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Hypoxia Inducible Factor ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Independent Manner ◽  
Von Hippel Lindau ◽  
Gsk 3Β

ABSTRACT Hypoxia-inducible transcription factor 1α (HIF-1α) is a key player in the response to hypoxia. Additionally, HIF-1α responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1α is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1α. We found that the inhibition or depletion of GSK-3 induced HIF-1α whereas the overexpression of GSK-3β reduced HIF-1α. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1α. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1α degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1α to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1α stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.

scholarly journals GSK-3β, a double-edged sword in Nrf2 regulation: Implications for neurological dysfunction and disease

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1043 ◽  
Author(s):  
Megan Culbreth ◽  
Michael Aschner
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Glycogen Synthase ◽  
Oxidative Stress Response ◽  
Neurological Dysfunction ◽  
Related Factor ◽  
Disease Etiology ◽  
Disease States ◽  
Attractive Therapeutic Target ◽  
Gsk 3Β

In the past decade, it has become evident that glycogen synthase kinase 3β (GSK-3β) modulates the nuclear factor erythroid 2-related factor 2 (Nrf2) oxidative stress response. GSK-3β functions as an inhibitor, both directly in the activation and indirectly in the post-induction of Nrf2. The incidence of oxidative stress in neurological dysfunction and disease has made this signaling pathway an attractive therapeutic target. There is minimal evidence, however, to support a distinctive function for GSK-3β mediated Nrf2 inhibition in nervous system decline, apart from the typical oxidative stress response. In both Alzheimer’s disease and brain ischemia, this pathway has been explored for potential benefits on disease etiology and advancement. Presently, it is unclear whether GSK-3β mediated Nrf2 inhibition markedly influences these disease states. Furthermore, the potential that each has unique function in neurodegenerative decline is unsubstantiated.

scholarly journals Inhibition of GSK-3β restores delayed gastric emptying in obesity-induced diabetic female mice

2020 ◽  
Vol 319 (4) ◽  
pp. G481-G493 ◽  
Author(s):  
Chethan Sampath ◽  
Shanthi Srinivasan ◽  
Michael L. Freeman ◽  
Pandu R. Gangula
Keyword(s):  
Gastric Emptying ◽  
Delayed Gastric Emptying ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Female Mice ◽  
Downstream Signaling ◽  
Gsk 3Β ◽  
Sb 216763 ◽  
Oxide Synthase

Inhibition of glycogen synthase kinase 3β (GSK-3β) with SB 216763 attenuates delayed gastric emptying through gastric nuclear factor erythroid 2-related factor 2 (Nrf2) -phase II enzymes in high-fat diet-fed female mice. SB 216763 restored impaired gastric PI3K/AKT/ β-catenin/caspase 3 expression. Inhibition of GSK-3β normalized gastric dihydrofolate reductase, neuronal nitric oxide synthase-α expression, dimerization and nitrergic relaxation. SB 216763 normalized both serum estrogen and nitrate levels in female obese/Type 2 diabetes mice. SB 216763 reduced downstream signaling of GSK-3β in enteric neuronal cells in vitro.

Abstract 80: Activation of Nrf2 by Sulforaphane via the AKT/GSK-3β/Fyn Pathway Prevents Angiotensin II-induced Cardiomyopathy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ying Xin ◽  
Yang Bai ◽  
Xin Jiang ◽  
Shanshan Zhou ◽  
Yuehui Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Nuclear Accumulation ◽  
Related Factor ◽  
Ang Ii ◽  
H9c2 Cells ◽  
Cardiac Damage ◽  
Gsk 3Β

Aims: Sulforaphane (SFN) as a nuclear factor erythroid 2-related factor 2 (Nrf2) activator protects the heart from, and deletion of the Nrf2 gene exaggerates, the effects of diabetes. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy; therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined. Methods and Results: The chronic cardiac effects of Ang II with and without SFN were examined in wild-type mice, transgenic Nrf2 knockout (Nrf2-KO) mice, and mice in which cardiac tissue overexpressed Nrf2 (Nrf2-TG). The signaling pathways of SFN-mediated Nrf2 activation were examined in H9C2 cells. Administration of a subpressor dose of Ang II to WT mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment, which also up-regulated Nrf2 expression and activation. Nrf2-TG mice showed resistance and Nrf2-KO mice displayed resistance to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of AKT, inhibition of glycogen synthase kinase (GSK)-3β, and increased nuclear accumulation of Fyn. In vitro up-regulation of Nrf2 by SFN in H9C2 cells was abolished and nuclear Fyn accumulation was increased when cells were exposed to a PI3K inhibitor or GSK-3β-specific activator. Conclusion: Nrf2 plays a central role in the prevention of Ang II-induced pathological effects, and SFN can prevent Ang II-induced cardiomyopathy through activation of Nrf2 partially via the AKT/GSK-3β/Fyn pathway.

scholarly journals Inhibition of TRIM32 Attenuates the Apoptosis, Oxidative Stress and Inflammatory Injury of Podocytes Induced by High Glucose by Affecting the Akt/GSK-3β/Nrf2 Pathway

2021 ◽  
Author(s):  
Zhao Chen ◽  
Lifang Tian ◽  
Li Wang ◽  
Xiaotao Ma ◽  
Fuqian Lei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Protective Effects ◽  
Gsk 3Β ◽  
Induced Apoptosis

Abstract Hyperglycemia-induced oxidative stress of podocytes exerts a major role in the pathological process of diabetic nephropathy. Tripartite motif-containing protein 32 (TRIM32) has been reported as a key protein in the modulation of cellular apoptosis and oxidative stress under various pathological processes. However, whether TRIM32 participates in the regulation of high glucose (HG)-induced injury in podocytes has not been investigated. The aims of this work were to assess the possible role of TRIM32 in mediating HG-induced apoptosis, oxidative stress and inflammatory response in podocytes in vitro. Herein, our results showed a marked increase in TRIM32 expression in HG-exposed podocytes. Loss-of-function experiments showed that the knockdown of TRIM32 improved the viability of HG-stimulated podocytes, and suppressed HG-induced apoptosis, oxidative stress and inflammatory response in podocytes. Further investigation revealed that the inhibition of TRIM32 enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling associated with modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis in podocytes following HG exposure. However, the suppression of Akt abrogated the TRIM32-knockdown-mediated activation of Nrf2 in HG-exposed podocytes. In addition, the knockdown of Nrf2 markedly abolished the TRIM32-inhibition-induced protective effects in HG-exposed podocytes. In summary, the results of this work show that the inhibition of TRIM32 protects podocytes from HG-induced injury by potentiating Nrf2 signaling via the modulation of Akt/GSK-3β signaling. This study indicates a potential role of TRIM32 in mediating podocyte injury during the progression of diabetic nephropathy.

scholarly journals Targeting Glycogen Synthase Kinase-3βfor Therapeutic Benefit against Oxidative Stress in Alzheimer's Disease: Involvement of the Nrf2-ARE Pathway

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Katja Kanninen ◽  
Anthony R. White ◽  
Jari Koistinaho ◽  
Tarja Malm
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Gsk 3Β

Specific regions of the Alzheimer's disease (AD) brain are burdened with extracellular protein deposits, the accumulation of which is concomitant with a complex cascade of overlapping events. Many of these pathological processes produce oxidative stress. Under normal conditions, oxidative stress leads to the activation of defensive gene expression that promotes cell survival. At the forefront of defence is the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates a broad spectrum of protective genes. Glycogen synthase kinase-3β (GSK-3β) regulates Nrf2, thus making this kinase a potential target for therapeutic intervention aiming to boost the protective activation of Nrf2. This paper aims to review the neuroprotective role of Nrf2 in AD, with special emphasis on the role of GSK-3β in the regulation of the Nrf2 pathway. We also examine the potential of inducing GSK-3β by small-molecule activators, dithiocarbamates, which potentially exert their beneficial therapeutic effects via the activation of the Nrf2 pathway.

scholarly journals Inactivation of glycogen synthase kinase 3β (GSK-3β) enhances mitochondrial biogenesis during myogenesis

2018 ◽  
Vol 1864 (9) ◽  
pp. 2913-2926 ◽  
Author(s):  
W.F. Theeuwes ◽  
H.R. Gosker ◽  
R.C.J. Langen ◽  
N.A.M. Pansters ◽  
A.M.W.J. Schols ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β
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