Role of AMP-activated protein kinase in autophagy and proteasome function

Viana, Rosa; Aguado, Carmen; Esteban, Inmaculada; Moreno, Daniel Antunes; Viollet, Benoı̂t; Knecht, Erwin; Sanz, Pascual

doi:10.1016/j.bbrc.2008.02.126

Cited by 67 publications

(56 citation statements)

References 27 publications

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“…A recent study with mouse and human endothelial cell cultures has demonstrated that AMPKα2 can modestly reduce proteasome activity; this likewise results in a downregulation of NF-kappaB activation . (A similar effect of AMPK on proteasomes has been reported in fibroblasts (Viana et al 2008).) This downregulation of NF-kappaB, in turn, results in decreased expression of various components of the NAPDH oxidase complex .…”

Section: Vascular Protectionsupporting

confidence: 74%

AMPK activation—protean potential for boosting healthspan

McCarty

2013

AGE

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AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP g e n e r a t i o n -m o s t n o t a b l y m e t f o r m i n a n d berberine-can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators-as reflected by their efficacy in diabetes management-regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of healthprotective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.

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Section: Vascular Protectionsupporting

confidence: 74%

AMPK activation—protean potential for boosting healthspan

McCarty

2013

AGE

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“…Activation has been shown to stimulate catabolism and inhibit fatty acid and cholesterol synthesis, with the net effect of reducing ATP consumption and promoting anaerobic ATP synthesis (21). AMPK activation has also been implicated in promoting cell survival by regulating macroautophagy (31,32).…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Protein Kinase Mediates Apoptosis in Response to Bioenergetic Stress through Activation of the Pro-apoptotic Bcl-2 Homology Domain-3-only Protein BMF

Kilbride

Farrelly

Bonner

et al. 2010

Journal of Biological Chemistry

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Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN)-HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPK␣ gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation.

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“…37 Moreover, it was shown that AMPK suppresses proteasome-dependent proteolysis in vitro. 22 Xu et al reported that proteasome-dependent degradation of GTPCH I was related to endothelial dysfunction in diabetes. 19 Wang et al reported that the inhibition of GTPCH I degradation by AMPK activation attenuated endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recent reports indicate that AMP-activated protein kinase (AMPK) suppresses proteasome-dependent protein degradation in vitro. 22 Moreover, some reports show that proteasome-dependent GTPCH I degradation is key for diabetesinduced endothelial dysfunction. 19,23 Therefore, we also investigated whether metformin, an oral hypoglycemic agent and AMPK activator, exerts a protective effect in diabetic nephropathy.…”

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confidence: 99%

Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy

Kidokoro

Satoh²,

Channon

et al. 2013

Journal of the American Society of Nephrology

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In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2 +/Akita diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2 +/Akita mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.

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Role of AMP-activated protein kinase in autophagy and proteasome function

Cited by 67 publications

References 27 publications

AMPK activation—protean potential for boosting healthspan

AMPK activation—protean potential for boosting healthspan

AMP-activated Protein Kinase Mediates Apoptosis in Response to Bioenergetic Stress through Activation of the Pro-apoptotic Bcl-2 Homology Domain-3-only Protein BMF

Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy

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