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Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1 ) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron path, leaving it kinetically stable to the vast majority of organic cellular metabolites. Show less

Mitochondria are among the most important cell organelles involved in the regulation of intracellular calcium homeostasis. During the last decade, a number of molecular structures responsible for the mitochondrial calcium transport have been identified including the mitochondrial Ca2+ uniporter (MCU), Na+/Ca2+ exchanger (NCLX), and Ca2+/H+ antiporter (Letm1). The review summarizes the data on the structure, regulation, and physiological role of such structures. The pathophysiological mechanism of Ca2+ transport through the cyclosporine A-sensitive mitochondrial permeability transition pore is discussed. An alternative mechanism for the mitochondrial pore opening, namely, formation of the lipid pore induced by saturated fatty acids, and its role in Ca2+ transport are described in detail. Show less

We here review the extraordinary mineralogical properties of green rusts and their naturally occurring form, fougerite, and discuss the pertinence of these properties within the alkaline hydrothermal vent (AHV) hypothesis for life's emergence. We put forward an extended version of the AHV scenario which enhances the conformity between extant life and its earliest progenitor by extensively making use of fougerite's mechanistic and catalytic particularities. Show less

Cell surface G-protein-coupled receptors (GPCRs) are targets for ∼ 30% of drugs currently on the market, and are the largest group of gene products targeted by drugs. Until recently, signaling mediated by GPCRs was thought to emanate exclusively from the cell membrane as a response to extracellular stimuli. However, recent research has revealed the existence of nuclear (n)GPCRs with the ability to trigger identical and/or distinct signaling pathways to their respective counterparts on the cell surface. Understanding of the GPCR signaling platform on the nuclear membranes and its involvement in physiology and/or pathophysiology will be important to develop selective pharmacological and pharmaceutical approaches. In this review, we summarize our current understanding of nGPCRs, with emphasis on their potential as novel pharmacological targets. Show less

The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies. Show less

Metabolic alterations in the tumor microenvironment have a complex effect on cancer progression. Extracellular acidity is a consequence of metabolic switch in cancer and results in cell phenotypes with higher resistance to chemotherapeutics. However, mechanisms underlying the relationship between the extracellular acidity and chemoresistance are not clearly understood. This systematic review was carried out by searching the databases PubMed and EMBASE using the keywords “cancer” and “acidosis” or “acidic” and “chemoresistance” or “drug resistance.” In vitro and in vivo studies that evaluated the effects of acidification of the tumor microenvironment on chemotherapeutic treatments were included. Literature reviews, letters to the editor, and articles that were not published in English were excluded. The search resulted in a total of 352 articles. After discarding 75 duplicate references, 277 articles were analyzed by sequentially reading through their titles, abstracts, and finally full-text. A total of 14 articles was selected. Acidification of the tumor microenvironment can trigger resistance through different mechanisms, such as increase in drug efflux transporters, inhibition of proton pumps, induction of the unfolded protein response (UPR), and cellular autophagy. Show less

Z-DNA is stabilized by various Z-DNA binding proteins (ZBPs) that play important roles in RNA editing, innate immune response, and viral infection. In this review, the structural and dynamics of various ZBPs complexed with Z-DNA are summarized to better understand the mechanisms by which ZBPs selectively recognize d(CG)-repeat DNA sequences in genomic DNA and efficiently convert them to left-handed Z-DNA to achieve their biological function. The intermolecular interaction of ZBPs with Z-DNA strands is mediated through a single continuous recognition surface which consists of an α3 helix and a β-hairpin. In the ZBP-Z-DNA complexes, three identical, conserved residues (N173, Y177, and W195 in the Zα domain of human ADAR1) play central roles in the interaction with Z-DNA. ZBPs convert a 6-base DNA pair to a Z-form helix via the B-Z transition mechanism in which the ZBP first binds to B-DNA and then shifts the equilibrium from B-DNA to Z-DNA, a conformation that is then selectively stabilized by the additional binding of a second ZBP molecule. During B-Z transition, ZBPs selectively recognize the alternating d(CG)n sequence and convert it to a Z-form helix in long genomic DNA through multiple sequence discrimination steps. In addition, the intermediate complex formed by ZBPs and B-DNA, which is modulated by varying conditions, determines the degree of B-Z transition. Show less

Metabolic reprogramming is one of the hallmarks of cancer. Nrf2 pathway is one of the critical signaling cascades involved in cell defense and survival against oxidative stress. The significance of Nrf2 in cancer metabolism begins to be recognized. In this minireview, we focus on the Nrf2-mediated cancer metabolic reprogramming and intend to highlight the role of Nrf2 in the regulation of malignant transformation, cancer proliferation, and the development of treatment resistance via metabolic adaptations. We hope for the development of noninvasive biomarkers and novel therapeutic approaches for cancer based on Nrf2-directed cancer metabolic reprogramming in the near future. Show less

In recent years, great progress has been made in understanding biology and pathogenesis of chronic lymphocytic leukemia. The key thing in disease pathogenesis is the apoptosis resistance of tumor cells. One of the main regulators of programmed cell death is the Bcl-2 family proteins. Important role of Bcl-2 protein in carcinogenesis made it an attractive target for therapeutic intervention. This review focuses on venetoclax (a selective inhibitor of the anti-apoptotic Bcl-2 protein) in the treatment of chronic lymphocytic leukemia. Show less

In the last few decades, a large body of experimental evidence has highlighted the complex role for mitochondria in eukaryotic cells: they are not only the site of aerobic metabolism (thus providing most of the ATP supply for endergonic processes) but also a crucial checkpoint of cell death processes (both necrosis and apoptosis) and autophagy. For this purpose, mitochondria must receive and decode the wide variety of physiological and pathological stimuli impacting on the cell. The "old" notion that mitochondria possess a sophisticated machinery for accumulating and releasing Ca 2+, the most common and versatile second messenger of eukaryotic cells, is thus no surprise. What may be surprising is that the identification of the molecules involved in mitochondrial Ca 2+ transport occurred only in the last decade for both the influx (the mitochondrial Ca 2+ uniporter, MCU) and the efflux (the sodium calcium exchanger, NCX) pathways. In this review, we will focus on the description of the amazing molecular complexity of the MCU complex, highlighting the numerous functional implications of the tissue-specific expression of the variants of the channel pore components (MCU/MCUb) and of the associated proteins (MICU 1, 2, and 3, EMRE, and MCUR1). Show less

Unperturbed transcription of eukaryotic genes by RNA polymerase II (Pol II) is crucial for proper cell function and tissue homeostasis. However, the DNA template of Pol II is continuously challenged by damaging agents that can result in transcription impediment. Stalling of Pol II on transcription-blocking lesions triggers a highly orchestrated cellular response to cope with these cytotoxic lesions. One of the first lines of defense is the transcription-coupled nucleotide excision repair (TC-NER) pathway that specifically removes transcription-blocking lesions thereby safeguarding unperturbed gene expression. In this perspective, we outline recent data on how lesion-stalled Pol II initiates TC-NER and we discuss new mechanistic insights in the TC-NER reaction, which have resulted in a better understanding of the causative-linked Cockayne syndrome and UV-sensitive syndrome. In addition to these direct effects on lesion-stalled Pol II (effects in cis), accumulating evidence shows that transcription, and particularly Pol II, is also affected in a genome-wide manner (effects in trans). We will summarize the diverse consequences of DNA damage on transcription, including transcription inhibition, induction of specific transcriptional programs and regulation of alternative splicing. Finally, we will discuss the function of these diverse cellular responses to transcription-blocking lesions and their consequences on the process of transcription restart. This resumption of transcription, which takes place either directly at the lesion or is reinitiated from the transcription start site, is crucial to maintain proper gene expression following removal of the DNA damage. Show less

Tetrazole cycle is a promising pharmacophore fragment frequently used in the development of novel drugs. This moiety is a stable, practically non-metabolized bioisosteric analog of carboxylic, cis-amide, and other functional groups. Over recent 10-15 years, various isomeric forms of tetrazole (NH-unsubstituted, 1H-1- substituted, and 2H-2-substituted tetrazoles) have been successfully used in the design of promising anticancer drugs. Coordination compounds of transition metals containing tetrazoles as ligands, semisynthetic tetrazolyl derivatives of natural compounds (biogenic acids, peptides, steroids, combretastatin, etc.), 5-oxo and 5- thiotetrazoles, and some other related compounds have been recognized as promising antineoplastic agents. This review presents a comprehensive analysis of modern approaches to synthesis of these tetrazole derivatives as well as their biological (anticancer) properties. The most promising structure types of tetrazoles to be used as anticancer agents have been picked out. Show less

The Kelch‐like ECH‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 (KEAP1‐NRF2) system is a pivotal defense mechanism against oxidative and electrophilic stress. Although transient NRF2 activation in response to stress is beneficial for health, persistent NRF2 activation in cancer cells has deleterious effects on cancer‐bearing hosts by conferring therapeutic resistance and aggressive tumorigenic activity on cancer cells. Because NRF2 increases the antioxidant and detoxification capability of cancer cells, persistently high levels of NRF2 activity enhance therapeutic resistance of cancer cells. NRF2 also drives metabolic reprogramming to establish cellular metabolic processes that are advantageous for cell proliferation in cooperation with other oncogenic pathways. As a result of these advantages, cancer cells with persistent activation of NRF2 often develop “NRF2 addiction” and show malignant phenotypes leading to poor prognoses in cancer patients. Inhibition of NRF2 is a promising therapeutic approach for NRF2‐addicted cancers and NRF2 inhibitors are being actively developed. However, giving systemic NRF2 inhibitors might have undesirable effects on cancer‐bearing hosts, considering the central roles of NRF2 in cytoprotection. To avoid these side‐effects, new therapeutic targets besides NRF2 for NRF2‐addicted cancers have been actively explored. This review introduces recent studies describing the development and characterization of NRF2‐addicted cancers, as well as their potential therapeutic targets. Expected advances in diagnostic and therapeutic interventions for NRF2‐addicted cancers are also discussed. Show less

Fumaric acid esters (FAEs) such as dimethylfumarate (DMF) are used for the treatment of adults with moderate-to-severe psoriasis. The mode of action of FAEs is complex. Here, we provide a comprehensive review of the literature to describe the molecular mechanisms by which DMF and its active metabolite monomethylfumarate (MMF) exert their anti-inflammatory and immune modulatory effects. MMF can bind to the hydroxy-carboxylic acid receptor 2 (HCA2) on the cell surface and both DMF and MMF react with intracellular glutathione following cell penetration. DMF and to some extent also MMF modulate the activity of certain cellular signalling proteins such as the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor kappa B (Nf-κB) and the cellular concentration of cyclic adenosine monophosphate. Some studies show that DMF can also affect the hypoxia-inducible factor 1-alpha (HIF-1α). These actions seem to be responsible for i) the downregulation of inflammatory cytokines and ii) an overall shift from a proinflammatory Th1/Th17 response to an anti-inflammatory/regulatory Th2 response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. There is a growing body of evidence to support the notion that DMF/MMF may also exert effects on granulocytes and non-immune cell lineages including keratinocytes and endothelial cells. A better understanding of the multiple molecular mechanisms involved in the cellular action of FAEs will help to adapt and further improve the use of such small molecules for the treatment of psoriasis and other chronic inflammatory diseases. Show less

The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor-promoting effects. Show less

Fe/S cluster biogenesis involves a complex machinery comprising several mitochondrial and cytosolic proteins. Fe/S cluster biosynthesis is closely intertwined with iron trafficking in the cell. Defects in Fe/S cluster elaboration result in severe diseases such as Friedreich ataxia. Deciphering this machinery is a challenge for the scientific community. Because iron is a key player, 57Fe-Mössbauer spectroscopy is especially appropriate for the characterization of Fe species and monitoring the iron distribution. This minireview intends to illustrate how Mössbauer spectroscopy contributes to unravel steps in Fe/S cluster biogenesis. Studies were performed on isolated proteins that may be present in multiple protein complexes. Since a few decades, Mössbauer spectroscopy was also performed on whole cells or on isolated compartments such as mitochondria and vacuoles, affording an overview of the iron trafficking. This minireview aims at presenting selected applications of 57Fe-Mössbauer spectroscopy to Fe/S cluster biogenesis. Show less

Abstract TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less

The nucleotide excision repair system removes a wide variety of DNA lesions from the human genome, including photoproducts induced by ultraviolet (UV) wavelengths of sunlight. A defining feature of nucleotide excision repair is its dual incision mechanism, in which two nucleolytic incision events on the damaged strand of DNA at sites bracketing the lesion generate a damage-containing DNA oligonucleotide and a single-stranded DNA gap approximately 30 nucleotides in length. Although the early events of nucleotide excision repair, which include lesion recognition and the dual incisions, have been explored in detail and are reasonably well understood, the fate of the single-stranded DNA gaps and excised oligonucleotide products of repair have not been as extensively examined. In this review, recent findings that address these less-explored aspects of nucleotide excision repair are discussed and support the concept that postincision gap and excised oligonucleotide processing are critical steps in the cellular response to DNA damage induced by UV light and other environmental carcinogens. Defects in these latter stages of repair lead to cell death and other DNA damage signaling responses and may therefore contribute to a number of human disease states associated with exposure to UV wavelengths of sunlight, including skin cancer, aging and autoimmunity. Show less

Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined. Show less

Despite substantial advances in the treatment of various cancers, many patients still receive anti-cancer therapies that hardly eradicate tumor cells but inflict considerable side effects. To provide the best treatment regimen for an individual patient, a major goal in molecular oncology is to identify predictive markers for a personalized therapeutic strategy. Regarding novel targeted anti-cancer therapies, there are usually good markers available. Unfortunately, however, targeted therapies alone often result in rather short remissions and little cytotoxic effect on the cancer cells. Therefore, classical chemotherapy with frequent long remissions, cures, and a clear effect on cancer cell eradication remains a corner stone in current anti-cancer therapy. Reliable biomarkers which predict the response of tumors to classical chemotherapy are rare, in contrast to the situation for targeted therapy. For the bulk of cytotoxic therapeutic agents, including DNA-damaging drugs, drugs targeting microtubules or antimetabolites, there are still no reliable biomarkers used in the clinic to predict tumor response. To make progress in this direction, meticulous studies of classical chemotherapeutic drug action and resistance mechanisms are required. For this purpose, novel functional screening technologies have emerged as successful technologies to study chemotherapeutic drug response in a variety of models. They allow a systematic analysis of genetic contributions to a drug-responsive or -sensitive phenotype and facilitate a better understanding of the mode of action of these drugs. These functional genomic approaches are not only useful for the development of novel targeted anti-cancer drugs but may also guide the use of classical chemotherapeutic drugs by deciphering novel mechanisms influencing a tumor's drug response. Moreover, due to the advances of 3D organoid cultures from patient tumors and in vivo screens in mice, these genetic screens can be applied using conditions that are more representative of the clinical setting. Patient-derived 3D organoid lines furthermore allow the characterization of the "essentialome", the specific set of genes required for survival of these cells, of an individual tumor, which could be monitored over the course of treatment and help understanding how drug resistance evolves in clinical tumors. Thus, we expect that these functional screens will enable the discovery of novel cancer-specific vulnerabilities, and through clinical validation, move the field of predictive biomarkers forward. This review focuses on novel advanced techniques to decipher the interplay between genetic alterations and drug response. Show less

Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less

Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less

Organometallic compounds currently occupy an important place in the field of medicinal inorganic chemistry due to the unique chemical properties of metal coordination compounds. Particularly, metal compounds ligated by N-heterocyclic carbenes (NHC) have shown high potential for biomedical applications as antimicrobial and anticancer agents during the recent 15 years. Although further studies are necessary to validate the modes of action of this family of compounds, a number of biological targets have been identified, including DNA secondary structures. This perspective review aims at providing an overview of the most representative examples of metal NHC complexes reacting with nucleic acids via different binding modes. It is organized according to the type of DNA secondary structure targeted by metal NHCs, highlighting the possible advantages of biomedical applications, including therapy and imaging. Show less

The nucleolus is the site of ribosome biogenesis, a complex process that requires the coordinate activity of all three RNA polymerases and hundreds of non-ribosomal factors that participate in the maturation of ribosomal RNA (rRNA) and assembly of small and large subunits. Nevertheless, emerging studies have highlighted the fundamental role of the nucleolus in sensing a variety of cellular stress stimuli that target ribosome biogenesis. This condition is known as nucleolar stress and triggers several response pathways to maintain cell homeostasis, either p53-dependent or p53-independent. The mouse double minute (MDM2)-p53 stress signaling pathways are activated by multiple signals and are among the most important regulators of cellular homeostasis. In this review, we will focus on the role of ribosomal proteins in p53-dependent and p53-independent response to nucleolar stress considering novel identified regulators of these pathways. We describe, in particular, the role of ribosomal protein uL3 (rpL3) in p53-independent nucleolar stress signaling pathways. Show less

BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites. CONTENT: D-2-hydroxyglutarate, L-2-hydroxyglutarate, succinate, and fumarate are the currently recognized oncometabolites. They are structurally similar and share metabolic proximity in the tricarboxylic acid cycle. As a result, they promote tumorigenesis in cancer cells through similar mechanisms. This review summarizes the currently understood common and distinct biological features of these compounds. In addition, we will review the current laboratory methodologies that can be used to quantify these metabolites and their downstream targets. SUMMARY: Oncometabolites play an important role in cancer biology. The metabolic pathways that lead to the production of oncometabolites and the downstream signaling pathways that are activated by oncometabolites represent potential therapeutic targets. Clinical laboratories have a critical role to play in the management of oncometabolite-associated cancers through development and validation of sensitive and specific assays that measure oncometabolites and their downstream effectors. These assays can be used as screening tools and for follow-up to measure response to treatment, as well as to detect minimal residual disease and recurrence. Show less

As anticipated in the title, this contribution is basically divided into two, strictly connected, parts. The first is a personal overview of the ruthenium drug candidate NAMI‐A, almost 30 years after its synthesis and the discovery of its unprecedented antimetastatic properties in animal models at nontoxic dosages. The sections relating to the chemical and biological behavior of the complex, and the hypotheses on its mechanism(s) of action, are kept to a minimum, whereas more space is devoted to discussion of the results of the clinical investigations. The second part deals in detail with a number of undemonstrated misconceptions (or myths) that, over the years, have thrived around NAMI‐A and other ruthenium drug candidates, thus negatively affecting the whole field of Ru anticancer drugs. Show less

Reactive Oxygen Species (ROS) can cause oxidative damage and have been proposed to be the main cause of ageing and age-related diseases including cancer, diabetes and Parkinson’s disease. Accordingly, mitochondria from old individuals have higher levels of ROS. However, ROS also participate in cellular signaling, are instrumental for several physiological processes and boosting ROS levels in model organisms extends lifespan. The current consensus is that low levels of ROS are beneficial, facilitating adaptation to stress via signalling, whereas high levels of ROS are deleterious because they trigger oxidative stress. Based on this model the amount of ROS should determine the physiological effect. However, recent data suggests that the site at which ROS are generated is also instrumental in determining effects on cellular homeostasis. The best example of site-specific ROS signaling is reverse electron transport (RET). RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of ROS. RET has been shown to be instrumental for the activation of macrophages in response to bacterial infection, re-organisation of the electron transport chain in response to changes in energy supply and adaptation of the carotid body to changes in oxygen levels. In Drosophila melanogaster, stimulating RET extends lifespan. Here, we review what is known about RET, as an example of site-specific ROS signaling, and its implications for the field of redox biology. Show less

Arginine methylation is a common post-translational modification functioning as an epigenetic regulator of transcription and playing key roles in pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision. Recently, a wealth of studies using transgenic mouse models and selective PRMT inhibitors helped define physiological roles for protein arginine methyltransferases (PRMTs) linking them to diseases such as cancer and metabolic, neurodegenerative, and muscular disorders. This review describes the recent molecular advances that have been uncovered in normal and diseased mammalian cells. Show less