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Regulation of Cell Function by AMPK and Sirtuins: From Basic...
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Regulation of Cell Function by AMPK and Sirtuins: From Basic Research to Disease and Aging

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Aging".

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Editors

Dr. Yury Ladilov

E-Mail Website
Collection Editor
Department of Cardiovascular Surgery, Heart Center Brandenburg, Brandenburg Medical School, 16321 Bernau, Germany
Interests: cAMP; AMPK; mitochondria; autophagy; heart failure; aging
Special Issues, Collections and Topics in MDPI journals
Dr. Muhammad Aslam

E-Mail Website
Collection Editor
Experimental Cardiology, Justus Liebig University Giessen, 35392 Giessen, Germany
Interests: vascular permeability; Rho GTPases; purinergic receptors; platelet biology; endothelial function; ROS
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Luisa Barcena

E-Mail Website
Collection Editor
Department of Geriatrics and Medical Gerontology, Charité, 12203 Berlin, Germany
Interests: cardiac aging; inflammaging; cardiac inflammation; mitochondrial function; cellular senescence; immunosenescence; immunometabolism
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

5'-AMP-activated protein kinase, or AMPK, is a multidimensional kinase that acts as an energy sensor, in addition to regulating numerous cellular processes involved in cell survival, health and lifespan. The close partners of AMPK are the sirtuins, a family of evolutionarily conserved NAD+-dependent protein deacetylases that are also widely considered to be metabolic sensors.  Remarkably, there is an interaction between AMPK and sirtuins. In particular, Sirt1 mediates AMPK activity via deacetylation and the activation of the upstream AMPK kinase LKB1. In turn, the activation of AMPK can lead to either the overexpression of some sirtuins or to the stimulation of their activity through increasing the cellular NAD+ level. AMPK and sirtuins are activated by energy-depleting/expending conditions, such as caloric restriction or exercise, and have similar effects on such diverse processes as cellular metabolism, inflammation and mitochondrial function.

Both AMPK activity and SIRT1 abundance/activity are reduced with aging, overnutrition or physical inactivity, which may lead to numerous pathologies and diseases, such as diabetes, cancer, inflammation and cardiovascular as well as neurodegenerative diseases. Therefore, understanding the mechanisms regulating the activity and expression of AMPK and sirtuins may provide a basis with which to fight diseases and aging-associated malfunctions. 

Authors are invited to submit manuscripts in all areas of current AMPK or sirtuins research, with an emphasis on basic as well as translational aspects. Studies addressing age-related changes in AMPK and sirtuin signaling are explicitly encouraged. This Topical Collection welcomes up-to-date hypotheses, reviews, research articles and short communications. Clinical studies, if relevant, as well as computational modeling are also welcome.

Dr. Yury Ladilov
Dr. Muhammad Aslam
Dr. Maria Luisa Barcena
Collection Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • AMPK
  • sirtuins
  • inflammation
  • aging
  • longevity
  • autophagy
  • mitophagy
  • cell signaling
  • mitochondrial function
  • exercise
  • fasting

Published Papers (7 papers)

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2023

Jump to: 2022

16 pages, 11667 KiB  
Article
Korean Red Ginseng-Induced SIRT3 Promotes the Tom22–HIF-1α Circuit in Normoxic Astrocytes
by Hyungsu Kim, Sunhong Moon, Dohyung Lee, Jinhong Park, Chang-Hee Kim, Young-Myeong Kim and Yoon Kyung Choi
Cells 2023, 12(11), 1512; https://doi.org/10.3390/cells12111512 - 30 May 2023
Cited by 1 | Viewed by 1220
Abstract
Astrocytes play a key role in brain functioning by providing energy to neurons. Increased astrocytic mitochondrial functions by Korean red ginseng extract (KRGE) have been investigated in previous studies. KRGE administration induces hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in astrocytes [...] Read more.
Astrocytes play a key role in brain functioning by providing energy to neurons. Increased astrocytic mitochondrial functions by Korean red ginseng extract (KRGE) have been investigated in previous studies. KRGE administration induces hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in astrocytes in the adult mouse brain cortex. VEGF expression can be controlled by transcription factors, such as the HIF-1α and estrogen-related receptor α (ERRα). However, the expression of ERRα is unchanged by KRGE in astrocytes of the mouse brain cortex. Instead, sirtuin 3 (SIRT3) expression is induced by KRGE in astrocytes. SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that resides in the mitochondria and maintains mitochondrial homeostasis. Mitochondrial maintenance requires oxygen, and active mitochondria enhance oxygen consumption, resulting in hypoxia. The effects of SIRT3 on HIF-1α-mediated mitochondria functions induced by KRGE are not well established. We aimed to investigate the relationship between SIRT3 and HIF-1α in KRGE-treated normoxic astrocyte cells. Without changing the expression of the ERRα, small interfering ribonucleic acid targeted for SIRT3 in astrocytes substantially lowers the amount of KRGE-induced HIF-1α proteins. Reduced proline hydroxylase 2 (PHD2) expression restores HIF-1α protein levels in SIRT3-depleted astrocytes in normoxic cells treated with KRGE. The translocation of outer mitochondrial membranes 22 (Tom22) and Tom20 is controlled by the SIRT3-HIF-1α axis, which is activated by KRGE. KRGE-induced Tom22 increased oxygen consumption and mitochondrial membrane potential, as well as HIF-1α stability through PHD2. Taken together, in normoxic astrocytes, KRGE-induced SIRT3 activated the Tom22–HIF-1α circuit by increasing oxygen consumption in an ERRα-independent manner. Full article
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13 pages, 3889 KiB  
Article
SIRT3 Deficiency Enhances Ferroptosis and Promotes Cardiac Fibrosis via p53 Acetylation
by Han Su, Aubrey C. Cantrell, Jian-Xiong Chen, Wei Gu and Heng Zeng
Cells 2023, 12(10), 1428; https://doi.org/10.3390/cells12101428 - 19 May 2023
Cited by 10 | Viewed by 2452
Abstract
Cardiac fibrosis plays an essential role in the development of diastolic dysfunction and contributes to heart failure with preserved ejection fraction (HFpEF). Our previous studies suggested Sirtuin 3 (SIRT3) as a potential target for cardiac fibrosis and heart failure. In the present study, [...] Read more.
Cardiac fibrosis plays an essential role in the development of diastolic dysfunction and contributes to heart failure with preserved ejection fraction (HFpEF). Our previous studies suggested Sirtuin 3 (SIRT3) as a potential target for cardiac fibrosis and heart failure. In the present study, we explored the role of SIRT3 in cardiac ferroptosis and its contribution to cardiac fibrosis. Our data showed that knockout of SIRT3 resulted in a significant increase in ferroptosis, with increased levels of 4-hydroxynonenal (4-HNE) and downregulation of glutathione peroxidase 4 (GPX-4) in the mouse hearts. Overexpression of SIRT3 significantly blunted ferroptosis in response to erastin, a known ferroptosis inducer, in H9c2 myofibroblasts. Knockout of SIRT3 resulted in a significant increase in p53 acetylation. Inhibition of p53 acetylation by C646 significantly alleviated ferroptosis in H9c2 myofibroblasts. To further explore the involvement of p53 acetylation in SIRT3-mediated ferroptosis, we crossed acetylated p53 mutant (p534KR) mice, which cannot activate ferroptosis, with SIRT3KO mice. SIRT3KO/p534KR mice exhibited a significant reduction in ferroptosis and less cardiac fibrosis compared to SIRT3KO mice. Furthermore, cardiomyocyte-specific knockout of SIRT3 (SIRT3-cKO) in mice resulted in a significant increase in ferroptosis and cardiac fibrosis. Treatment of SIRT3-cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) led to a significant reduction in ferroptosis and cardiac fibrosis. We concluded that SIRT3-mediated cardiac fibrosis was partly through a mechanism involving p53 acetylation-induced ferroptosis in myofibroblasts. Full article
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2022

Jump to: 2023

15 pages, 2739 KiB  
Article
SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice
by Tomoya Mizumoto, Tatsuya Yoshizawa, Yoshifumi Sato, Takaaki Ito, Tomonori Tsuyama, Akiko Satoh, Satoshi Araki, Kenichi Tsujita, Masaru Tamura, Yuichi Oike and Kazuya Yamagata
Cells 2022, 11(22), 3609; https://doi.org/10.3390/cells11223609 - 15 Nov 2022
Cited by 5 | Viewed by 2293
Abstract
Sirtuins (SIRT1–7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the [...] Read more.
Sirtuins (SIRT1–7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency. Full article
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15 pages, 2474 KiB  
Article
Arginine Reduces Glycation in γ2 Subunit of AMPK and Pathologies in Alzheimer’s Disease Model Mice
by Rui Zhu, Ying Lei, Fangxiao Shi, Qing Tian and Xinwen Zhou
Cells 2022, 11(21), 3520; https://doi.org/10.3390/cells11213520 - 07 Nov 2022
Cited by 3 | Viewed by 1570
Abstract
The metabolism disorders are a common convergence of Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). The characteristics of AD are senile plaques and neurofibrillary tangles (NFTs) composed by deposits of amyloid−β (Aβ) and phosphorylated tau, respectively. Advanced glycation end−products (AGEs) are [...] Read more.
The metabolism disorders are a common convergence of Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). The characteristics of AD are senile plaques and neurofibrillary tangles (NFTs) composed by deposits of amyloid−β (Aβ) and phosphorylated tau, respectively. Advanced glycation end−products (AGEs) are a stable modification of proteins by non−enzymatic reactions, which could result in the protein dysfunction. AGEs are associated with some disease developments, such as diabetes mellitus and AD, but the effects of the glycated γ2 subunit of AMPK on its activity and the roles in AD onset are unknown. Methods: We studied the effect of glycated γ2 subunit of AMPK on its activity in N2a cells. In 3 × Tg mice, we administrated L−arginine once every two days for 45 days and evaluated the glycation level of γ2 subunit and function of AMPK and alternation of pathologies. Results: The glycation level of γ2 subunit was significantly elevated in 3 × Tg mice as compared with control mice, meanwhile, the level of pT172−AMPK was obviously lower in 3 × Tg mice than that in control mice. Moreover, we found that arginine protects the γ2 subunit of AMPK from glycation, preserves AMPK function, and improves pathologies and cognitive deficits in 3 × Tg mice. Conclusions: Arginine treatment decreases glycated γ2 subunit of AMPK and increases p−AMPK levels in 3 × Tg mice, suggesting that reduced glycation of the γ2 subunit could ameliorate AMPK function and become a new target for AD therapy in the future. Full article
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42 pages, 6414 KiB  
Article
Obligatory Role of AMPK Activation and Antioxidant Defense Pathway in the Regulatory Effects of Metformin on Cellular Protection and Prevention of Lens Opacity
by Bhavana Chhunchha, Eri Kubo and Dhirendra P. Singh
Cells 2022, 11(19), 3021; https://doi.org/10.3390/cells11193021 - 27 Sep 2022
Cited by 4 | Viewed by 2203
Abstract
Increasing levels of oxidative-stress due to deterioration of the Nrf2 (NFE2-related factor)/ARE (antioxidant response element) pathway is found to be a primary cause of aging pathobiology. Metformin having anti-aging effects can delay/halt aging-related diseases. Herein, using lens epithelial cell lines (LECs) of human [...] Read more.
Increasing levels of oxidative-stress due to deterioration of the Nrf2 (NFE2-related factor)/ARE (antioxidant response element) pathway is found to be a primary cause of aging pathobiology. Metformin having anti-aging effects can delay/halt aging-related diseases. Herein, using lens epithelial cell lines (LECs) of human (h) or mouse (m) and aging h/m primary LECs along with lenses as model systems, we demonstrated that Metformin could correct deteriorated Bmal1/Nrf2/ARE pathway by reviving AMPK-activation, and transcriptional activities of Bmal1/Nrf2, resulting in increased antioxidants enzymatic activity and expression of Phase II enzymes. This ensued reactive oxygen species (ROS) mitigation with cytoprotection and prevention of lens opacity in response to aging/oxidative stress. It was intriguing to observe that Metformin internalized lens/LECs and upregulated OCTs (Organic Cation Transporters). Mechanistically, we found that Metformin evoked AMPK activation-dependent increase of Bmal1, Nrf2, and antioxidants transcription by promoting direct E-Box and ARE binding of Bmal1 and Nrf2 to the promoters. Loss-of-function and disruption of E-Box/ARE identified that Metformin acted by increasing Bmal1/Nrf2-mediated antioxidant expression. Data showed that AMPK-activation was a requisite for Bmal1/Nrf2-antioxidants-mediated defense, as pharmacologically inactivating AMPK impeded the Metformin’s effect. Collectively, the results for the first-time shed light on the hitherto incompletely uncovered crosstalk between the AMPK and Bmal1/Nrf2/antioxidants mediated by Metformin for blunting oxidative/aging-linked pathobiology. Full article
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13 pages, 630 KiB  
Review
Sirtuin 1 in Host Defense during Infection
by Jin Kyung Kim, Prashanta Silwal and Eun-Kyeong Jo
Cells 2022, 11(18), 2921; https://doi.org/10.3390/cells11182921 - 19 Sep 2022
Cited by 8 | Viewed by 4124
Abstract
Sirtuins (SIRTs) are members of the class III histone deacetylase family and epigenetically control multiple target genes to modulate diverse biological responses in cells. Among the SIRTs, SIRT1 is the most well-studied, with a role in the modulation of immune and inflammatory responses [...] Read more.
Sirtuins (SIRTs) are members of the class III histone deacetylase family and epigenetically control multiple target genes to modulate diverse biological responses in cells. Among the SIRTs, SIRT1 is the most well-studied, with a role in the modulation of immune and inflammatory responses following infection. The functions of SIRT1 include orchestrating immune, inflammatory, metabolic, and autophagic responses, all of which are required in establishing and controlling host defenses during infection. In this review, we summarize recent information on the roles of SIRT1 and its regulatory mechanisms during bacterial, viral, and parasitic infections. We also discuss several SIRT1 modulators, as potential antimicrobial treatments. Understanding the function of SIRT1 in balancing immune homeostasis will contribute to the development of new therapeutics for the treatment of infection and inflammatory disease. Full article
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23 pages, 4047 KiB  
Article
The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism
by Sonia Spinelli, Lucrezia Guida, Tiziana Vigliarolo, Mario Passalacqua, Giulia Begani, Mirko Magnone, Laura Sturla, Andrea Benzi, Pietro Ameri, Edoardo Lazzarini, Claudia Bearzi, Roberto Rizzi and Elena Zocchi
Cells 2022, 11(18), 2888; https://doi.org/10.3390/cells11182888 - 15 Sep 2022
Cited by 10 | Viewed by 2413
Abstract
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We [...] Read more.
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia. Full article
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