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Metabolic Reprogramming in Health and Disease
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Metabolic Reprogramming in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 36677

Special Issue Editor

Dr. Grazia Chiellini

E-Mail Website
Guest Editor
Department of Surgical Pathology, Università di Pisa, Pisa, Italy
Interests: metabolic biochemistry; thyroid hormone analogs and metabolites; vitamin D analogs; drug design, synthesis and development

Special Issue Information

Dear Colleagues,

Metabolism is broadly defined as the sum of biochemical processes in living organisms that either produce or consume energy.

It is widely acknowledged that metabolic perturbations—often genetically programmed—accompany common human diseases. Among these, cancer is a prime example of a disease with genetically-defined, pathological metabolic perturbations. Indeed, metabolic reprogramming, such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid (TCA) cycle metabolic enzymes, and dependence on lipid and glutamine metabolism are key characteristics of cancer cells. Therefore, addressing such metabolic perturbations is a very promising direction for anti-cancer therapies that, in combination with conventional chemotherapeutic agents, may enhance therapeutic efficacy and clinical outcomes.

One of the main challenges in human metabolism research is to analyze the impact of disease on metabolic flux in vivo, by relaying on the use of sensitive and efficient methods, such as NMR spectroscopy or mass spectrometry techniques, to measure the transfer of carbon, nitrogen, etc., along metabolic pathways in live subjects, with and without disease. These approaches are growing in use and will likely find key applications in understanding the metabolic basis of common human diseases, paving the way for the translation of this knowledge into novel diagnostic and therapeutic approaches.

This Special Issue of the International Journal of Molecular Sciences, “Metabolic Reprogramming in Health and Disease”, will focus on the broad impact of metabolism in cellular function, and how modern concepts of metabolism can inform our understanding of common diseases, including cancer, obesity, diabetes and neurodegenerative disorders, and considers the prospects of developing new metabolic approaches to disease treatment.

Authors are invited to contribute a full original research paper or review article for peer-review and publication.

Dr. Grazia Chiellini
Guest Editor

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 special issue 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • metabolic reprogramming
  • cancer metabolism
  • metabolic enzymes
  • energy metabolism
  • cell signaling
  • metabolomics

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 157 KiB  
Editorial
Metabolic Reprogramming in Health and Disease
by Grazia Chiellini
Int. J. Mol. Sci. 2020, 21(8), 2768; https://doi.org/10.3390/ijms21082768 - 16 Apr 2020
Cited by 3 | Viewed by 2373
Abstract
This editorial aims to summarize the six scientific papers that contributed to this Special Issue. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)

Research

Jump to: Editorial, Review

14 pages, 2112 KiB  
Article
Doxorubicin Inhibits Phosphatidylserine Decarboxylase and Modifies Mitochondrial Membrane Composition in HeLa Cells
by Nadège Bellance, Fabienne Furt, Su Melser, Claude Lalou, Didier Thoraval, Lilly Maneta-Peyret, Didier Lacombe, Patrick Moreau and Rodrigue Rossignol
Int. J. Mol. Sci. 2020, 21(4), 1317; https://doi.org/10.3390/ijms21041317 - 15 Feb 2020
Cited by 15 | Viewed by 4628
Abstract
Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II. However, few studies have reported the mitochondrial effects of DXR while investigating cardiac toxicity induced by the treatment, [...] Read more.
Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II. However, few studies have reported the mitochondrial effects of DXR while investigating cardiac toxicity induced by the treatment, mostly in pediatric cases. Here, we demonstrate that DXR alters the mitochondrial membrane composition associated with bioenergetic impairment and cell death in human cancer cells. The remodeling of the mitochondrial membrane was explained by phosphatidylserine decarboxylase (PSD) inhibition by DXR. PSD catalyzes phosphatidylethanolamine (PE) synthesis from phosphatidylserine (PS), and DXR altered the PS/PE ratio in the mitochondrial membrane. Moreover, we observed that DXR localized to the mitochondrial compartment and drug uptake was rapid. Evaluation of other topoisomerase II inhibitors did not show any impact on the mitochondrial membrane composition, indicating that the DXR effect was specific. Therefore, our findings revealed a side molecular target for DXR and PSD, potentially involved in DXR anti-cancer properties and the associated toxicity. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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20 pages, 3461 KiB  
Article
Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
by Sarah Paisdzior, Ioanna Maria Dimitriou, Paul Curtis Schöpe, Paolo Annibale, Patrick Scheerer, Heiko Krude, Martin J. Lohse, Heike Biebermann and Peter Kühnen
Int. J. Mol. Sci. 2020, 21(4), 1224; https://doi.org/10.3390/ijms21041224 - 12 Feb 2020
Cited by 27 | Viewed by 6264
Abstract
The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated [...] Read more.
The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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16 pages, 4437 KiB  
Article
O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension
by Jarrod W. Barnes, Liping Tian, Stefanie Krick, E. Scott Helton, Rebecca S. Denson, Suzy A. A. Comhair and Raed A. Dweik
Int. J. Mol. Sci. 2019, 20(24), 6299; https://doi.org/10.3390/ijms20246299 - 13 Dec 2019
Cited by 21 | Viewed by 4471
Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked [...] Read more.
Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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14 pages, 3749 KiB  
Article
Swim Training Modulates Mouse Skeletal Muscle Energy Metabolism and Ameliorates Reduction in Grip Strength in a Mouse Model of Amyotrophic Lateral Sclerosis
by Damian Jozef Flis, Katarzyna Dzik, Jan Jacek Kaczor, Karol Cieminski, Malgorzata Halon-Golabek, Jedrzej Antosiewicz, Mariusz Roman Wieckowski and Wieslaw Ziolkowski
Int. J. Mol. Sci. 2019, 20(2), 233; https://doi.org/10.3390/ijms20020233 - 9 Jan 2019
Cited by 21 | Viewed by 5202
Abstract
Metabolic reprogramming in skeletal muscles in the human and animal models of amyotrophic lateral sclerosis (ALS) may be an important factor in the diseases progression. We hypothesized that swim training, a modulator of cellular metabolism via changes in muscle bioenergetics and oxidative stress, [...] Read more.
Metabolic reprogramming in skeletal muscles in the human and animal models of amyotrophic lateral sclerosis (ALS) may be an important factor in the diseases progression. We hypothesized that swim training, a modulator of cellular metabolism via changes in muscle bioenergetics and oxidative stress, ameliorates the reduction in muscle strength in ALS mice. In this study, we used transgenic male mice with the G93A human SOD1 mutation B6SJL-Tg (SOD1G93A) 1Gur/J and wild type B6SJL (WT) mice. Mice were subjected to a grip strength test and isolated skeletal muscle mitochondria were used to perform high-resolution respirometry. Moreover, the activities of enzymes involved in the oxidative energy metabolism and total sulfhydryl groups (as an oxidative stress marker) were evaluated in skeletal muscle. ALS reduces muscle strength (−70% between 11 and 15 weeks, p < 0.05), modulates muscle metabolism through lowering citrate synthase (CS) (−30% vs. WT, p = 0.0007) and increasing cytochrome c oxidase and malate dehydrogenase activities, and elevates oxidative stress markers in skeletal muscle. Swim training slows the reduction in muscle strength (−5% between 11 and 15 weeks) and increases CS activity (+26% vs. ALS I, p = 0.0048). Our findings indicate that swim training is a modulator of skeletal muscle energy metabolism with concomitant improvement of skeletal muscle function in ALS mice. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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Review

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19 pages, 1579 KiB  
Review
3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?
by Grazia Rutigliano, Lavinia Bandini, Simona Sestito and Grazia Chiellini
Int. J. Mol. Sci. 2020, 21(6), 2005; https://doi.org/10.3390/ijms21062005 - 15 Mar 2020
Cited by 16 | Viewed by 3779
Abstract
In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties [...] Read more.
In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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Graphical abstract

23 pages, 1287 KiB  
Review
Tumor Microenvironment: A Metabolic Player that Shapes the Immune Response
by Shamir Cassim and Jacques Pouyssegur
Int. J. Mol. Sci. 2020, 21(1), 157; https://doi.org/10.3390/ijms21010157 - 25 Dec 2019
Cited by 150 | Viewed by 9382
Abstract
Immune cells survey and patrol throughout the body and sometimes take residence in niche environments with distinct cellular subtypes and nutrients that may fluctuate from those in which they matured. Rooted in immune cell physiology are metabolic pathways and metabolites that not only [...] Read more.
Immune cells survey and patrol throughout the body and sometimes take residence in niche environments with distinct cellular subtypes and nutrients that may fluctuate from those in which they matured. Rooted in immune cell physiology are metabolic pathways and metabolites that not only deliver substrates and energy for growth and survival, but also instruct effector functions and cell differentiation. Unlike cancer cells, immune cells are not subject to a “Darwinian evolutionary pressure” that would allow them to adapt to developing tumors but are often irrevocably affected to local nutrient deprivation. Thus, immune cells must metabolically adapt to these changing conditions in order to perform their necessary functions. On the other hand, there is now a growing appreciation that metabolic changes occurring in cancer cells can impact on immune cell functionality and contribute to tumor immune evasion, and as such, there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy. In this review, we discuss the metabolic plasticity displayed by innate and adaptive immune cells and highlight how tumor-derived lactate and tumor acidity restrict immunity. To our knowledge, this review outlines the most recent insights on how tumor microenvironment metabolically instructs immune responsiveness. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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