Oxidative Post-translational Modifications Research Articles

Stable oxidative posttranslational modifications alter the gating properties of RyR1.

The ryanodine receptor type 1 (RyR1) is a Ca2+ release channel that regulates skeletal muscle contraction by controlling Ca2+ release from the sarcoplasmic reticulum (SR). Posttranslational modifications (PTMs) of RyR1, such as phosphorylation, S-nitrosylation, and carbonylation are known to increase RyR1 open probability (Po), contributing to SR Ca2+ leak and skeletal muscle dysfunction. PTMs on RyR1 have been linked to muscle dysfunction in diseases like breast cancer, rheumatoid arthritis, Duchenne muscle dystrophy, and aging. While reactive oxygen species (ROS) and oxidative stress induce PTMs, the impact of stable oxidative modifications like 3-nitrotyrosine (3-NT) and malondialdehyde adducts (MDA) on RyR1 gating remains unclear. Mass spectrometry and single-channel recordings were used to study how 3-NT and MDA modify RyR1 and affect Po. Both modifications increased Po in a dose-dependent manner, with mass spectrometry identifying 30 modified residues out of 5035 amino acids per RyR1 monomer. Key modifications were found in domains critical for protein interaction and channel activation, including Y808/3NT in SPRY1, Y1081/3NT and H1254/MDA in SPRY2&3, and Q2107/MDA and Y2128/3NT in JSol, near the binding site of FKBP12. Though these modifications did not directly overlap with FKBP12 binding residues, they promoted FKBP12 dissociation from RyR1. These findings provide detailed insights into how stable oxidative PTMs on RyR1 residues alter channel gating, advancing our understanding of RyR1-mediated Ca2+ release in conditions associated with oxidative stress and muscle weakness.

Insulin oxidation and oxidative modifications alter glucose uptake, cell metabolism, and inflammatory secretion profiles

Insulin participates in glucose homeostasis in the body and regulates glucose, protein, and lipid metabolism. Chronic hyperglycemia triggers oxidative stress and the generation of reactive oxygen species (ROS), leading to oxidized insulin variants. Oxidative protein modifications can cause functional changes or altered immunogenicity as known from the context of autoimmune disorders. However, studies on the biological function of native and oxidized insulin on glucose homeostasis and cellular function are lacking. Native insulin showed heterogenous effects on metabolic activity, proliferation, glucose carrier transporter (GLUT) 4, and insulin receptor (INSR) expression, as well as glucose uptake in cell lines of five different human tissues. Diverse ROS compositions produced by different gas plasma approaches enabled the investigations of variously modified insulin (oxIns) with individual oxidative post-translational modification (oxPTM) patterns as identified using high-resolution mass spectrometric analysis. Specific oxIns variants promoted cellular metabolism and proliferation in several cell lines investigated, and nitrogen plasma emission lines could be linked to insulin nitration and elevated glucose uptake. In addition, insulin oxidation modified blood glucose levels in the chicken embryos (in ovo), underlining the importance of assessing protein oxidation and function in health and disease.

Strain-dependent glutathionylation of fibronectin fibers impacts mechano-chemical behavior and primes an integrin switch

The extracellular matrix (ECM) is a protein polymer network that physically supports cells within a tissue. It acts as an important physical and biochemical stimulus directing cell behaviors. For fibronectin (Fn), a predominant component of the ECM, these physical and biochemical activities are inextricably linked as physical forces trigger conformational changes that impact its biochemical activity. Here, we analyze whether oxidative post-translational modifications, specifically glutathionylation, alter Fn’s mechano-chemical characteristics through stretch-dependent protein modification. ECM post-translational modifications represent a potential for time- or stimulus-dependent changes in ECM structure-function relationships that could persist over time with potentially significant impacts on cell and tissue behaviors. In this study, we show evidence that glutathionylation of Fn ECM fibers is stretch-dependent and alters Fn fiber mechanical properties with implications on the selectivity of engaging integrin receptors. These data demonstrate the existence of multimodal post-translational modification mechanisms within the ECM with high relevance to the microenvironmental regulation of downstream cell behaviors.

Quantification of persulfidation on specific proteins: are we nearly there yet?

Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function.

Cysteine sulfenylation contributes to liver fibrosis via the regulation of EphB2-mediated signaling

Sulfenylation is a reversible oxidative posttranslational modification (PTM) of proteins on cysteine residues. Despite the dissection of various biological functions of cysteine sulfenylation, its roles in hepatic fibrosis remain elusive. Here, we report that EphB2, a receptor tyrosine kinase previously implicated in liver fibrosis, is regulated by cysteine sulfenylation during the fibrotic progression of liver. Specifically, EphB2 is sulfenylated at the residues of Cys636 and Cys862 in activated hepatic stellate cells (HSCs), leading to the elevation of tyrosine kinase activity and protein stability of EphB2 and stronger interactions with focal adhesion kinase for the activation of downstream mitogen-activated protein kinase signaling. The inhibitions of both EphB2 kinase activity and cysteine sulfenylation by idebenone (IDE), a marketed drug with potent antioxidant activity, can markedly suppress the activation of HSCs and ameliorate hepatic injury in two well-recognized mouse models of liver fibrosis. Collectively, this study reveals cysteine sulfenylation as a new type of PTM for EphB2 and sheds a light on the therapeutic potential of IDE for the treatment of liver fibrosis.

Synthesis, Characterization, and Reactivity of a Synthetic End-On Cobalt(II) Alkyl Persulfide Complex as a Model Platform for Thiolate Persulfidation.

Persulfides (RSS-) are ubiquitous source of sulfides (S2-) in biology, and interactions between RSS- and bioinorganic metal centers play critical roles in biological hydrogen sulfide (H2S) biogenesis, signaling, and catabolism. Here, we report the use of contact-ion stabilized [Na(15-crown-5)][tBuSS] (1) as a simple synthon to access rare metal alkyl persulfide complexes and to investigate the reactivity of RSS- with transition metal centers to provide insights into metal thiolate persulfidation, including the fundamental difference between alkyl persulfides and alkyl thiolates. Reaction of 1 with [CoII(TPA)(OTf)]+ afforded the η1-alkyl persulfide complex [CoII(TPA)(SStBu)]+ (2), which was characterized by X-ray crystallography, UV-vis spectroscopy, and Raman spectroscopy. RSS- coordination to the Lewis acidic Co2+ center provided additional stability to the S-S bond, as evidenced by a significant increase in the Raman stretching frequency for 2 (vS-S = 522 cm-1, ΔvS-S = 66 cm-1). The effect of persulfidation on metal center redox potentials was further elucidated using cyclic voltammetry, in which the Co2+ → Co3+ oxidation potential of 2 (Ep,a = +89 mV vs SCE) is lowered by nearly 700 mV when compared to the corresponding thiolate complex [CoII(TPA)(StBu)]+ (3) (Ep,a = +818 mV vs SCE), despite persulfidation being generally seen as an oxidative post-translational modification. The reactivity of 2 toward reducing agents including PPh3, BH4-, and biologically relevant thiol reductant DTT led to different S2- output pathways, including formation of a dinuclear 2Co-2SH complex [CoII2(TPA)2(μ2-SH)2]2+(4).

Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.

Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.

Common metabolism and transcription responses of low-cadmium-accumulative wheat (Triticum aestivum L.) cultivars sprayed with nano-selenium

Cadmium (Cd) contamination in soils threatens food security, while cultivating low-Cd-accumulative varieties, coupled with agro-nanotechnology, offers a potential solution to reduce Cd accumulation in crops. Herein, foliar application of selenium nanoparticles (SeNPs) was performed on seedlings of two low-Cd-accumulative wheat (Triticum aestivum L.) varieties grown in soil spiked with Cd at 3 mg/kg. Results showed that foliar application of SeNPs at 0.16 mg/plant (SeNPs-M) significantly decreased the Cd content in leaves of XN-979 and JM-22 by 46.4 and 40.8 %, and alleviated oxidative damage. The wheat leaves treated with SeNPs-M underwent significant metabolic and transcriptional reprogramming. On one hand, four specialized antioxidant metabolites such as L-Tyrosine, beta-N-acetylglucosamine, D-arabitol, and monolaurin in response to SeNPs in JM-22 and XN-979 is the one reason for the decrease of Cd in wheat leaves. Moreover, alleviation of stress-related kinases, hormones, and transcription factors through oxidative post-translational modification, subsequently regulates the expression of defense genes via Se-enhanced glutathione peroxidase. These findings indicate that combining low-Cd-accumulative cultivars with SeNPs spraying is an effective strategy to reduce Cd content in wheat and promote sustainable agricultural development.

Trioxidized cysteine and aging: a molecular binomial that extends far beyond classical proteinopathic paradigms.

Increased oxidative stress (OS) and the disruption of the equilibrium between the production of reactive oxygen species and antioxidants are key molecular features of unhealthy aging. OS results in the formation of oxidative posttranslational modifications (PTMs), some of which involve cysteine (Cys) residues in aging proteomes, and specifically, the formation of trioxidized Cys (t-Cys), which leads to permanent protein damage. Recent findings in rodents have uncovered that irregular regulation of t-Cys residues in the aging proteome disrupts homeostatic phosphorylation signaling, resulting in alterations to proteins that are analogous to those caused by phosphorylated serine (p-Ser) residues. This work contextualizes these significant findings and discusses the implications and molecular role(s) of t-Cys in the aging proteome. Furthermore, we present novel data, validating the increase of specific t-Cys sites associated with aging in a blood-related circulating human proteome. The scope and findings included here support the hypothesis that t-Cys residues may serve as important mechanistic and biological markers, warranting further exploration in the context of unhealthy aging and age-related major diseases.

Oxidized Melanoma Antigens Promote Activation and Proliferation of Cytotoxic T-Cell Subpopulations.

Increasing evidence suggests the role of reactive oxygen and nitrogen species (RONS) in regulating antitumor immune effects and immunosuppression. RONS modify biomolecules and induce oxidative post-translational modifications (oxPTM) on proteins that can alarm phagocytes. However, it is unclear if and how protein oxidation by technical means could be a strategy to foster antitumor immunity and therapy. To this end, cold gas plasma technology producing various RONS simultaneously to oxidize the two melanoma-associated antigens MART and PMEL is utilized. Cold plasma-oxidized MART (oxMART) and PMEL (oxPMEL) are heavily decorated with oxPTMs as determined by mass spectrometry. Immunization with oxidized MART or PMEL vaccines prior to challenge with viable melanoma cells correlated with significant changes in cytokine secretion and altered T-cell differentiation of tumor-infiltrated leukocytes (TILs). oxMART promoted the activity of cytotoxic central memory T-cells, while oxPMEL led to increased proliferation of cytotoxic effector T-cells. Similar T-cell results are observed after incubating splenocytes of tumor-bearing mice with B16F10 melanoma cells. This study, for the first time, provides evidence of the importance of oxidative modifications of two melanoma-associated antigens in eliciting anticancer immunity.

S100A1's single cysteine is an indispensable redox switch for the protection against diastolic calcium waves in cardiomyocytes.

The EF-hand calcium (Ca2+) sensor protein S100A1 combines inotropic with antiarrhythmic potency in cardiomyocytes (CMs). Oxidative posttranslational modification (ox-PTM) of S100A1's conserved, single-cysteine residue (C85) via reactive nitrogen species (i.e., S-nitrosylation or S-glutathionylation) has been proposed to modulate conformational flexibility of intrinsically disordered sequence fragments and to increase the molecule's affinity toward Ca2+. Considering the unknown biological functional consequence, we aimed to determine the impact of the C85 moiety of S100A1 as a potential redox switch. We first uncovered that S100A1 is endogenously glutathionylated in the adult heart in vivo. To prevent glutathionylation of S100A1, we generated S100A1 variants that were unresponsive to ox-PTMs. Overexpression of wild-type (WT) and C85-deficient S100A1 protein variants in isolated CM demonstrated equal inotropic potency, as shown by equally augmented Ca2+ transient amplitudes under basal conditions and β-adrenergic receptor (βAR) stimulation. However, in contrast, ox-PTM defective S100A1 variants failed to protect against arrhythmogenic diastolic sarcoplasmic reticulum (SR) Ca2+ waves and ryanodine receptor 2 (RyR2) hypernitrosylation during βAR stimulation. Despite diastolic performance failure, C85-deficient S100A1 protein variants exerted similar Ca2+-dependent interaction with the RyR2 than WT-S100A1. Dissecting S100A1's molecular structure-function relationship, our data indicate for the first time that the conserved C85 residue potentially acts as a redox switch that is indispensable for S100A1's antiarrhythmic but not its inotropic potency in CMs. We, therefore, propose a model where C85's ox-PTM determines S100A1's ability to beneficially control diastolic but not systolic RyR2 activity.NEW & NOTEWORTHY S100A1 is an emerging candidate for future gene-therapy treatment of human chronic heart failure. We aimed to study the significance of the conserved single-cysteine 85 (C85) residue in cardiomyocytes. We show that S100A1 is endogenously glutathionylated in the heart and demonstrate that this is dispensable to increase systolic Ca2+ transients, but indispensable for mediating S100A1's protection against sarcoplasmic reticulum (SR) Ca2+ waves, which was dependent on the ryanodine receptor 2 (RyR2) nitrosylation status.

Hydrogen peroxide positively regulates ABA signaling via oxidative modification of the C2H2-type zinc finger protein ZFP36 in rice

The rice zinc finger protein ZFP36 serves as a pivotal regulator of the hydrogen peroxide (H2O2) signaling pathway in response to abscisic acid (ABA). Its role is crucial for integrating H2O2 signals with the plant defense mechanisms against water deficit and oxidative stress. However, it remains unclear whether ZFP36 directly modulates ABA-induced H2O2 signaling. This study explored the effects of oxidative post-translational modifications (OxiPTMs) on ZFP36 in rice, with an emphasis on the H2O2-induced oxidation through its cysteine (Cys) residues. We found that ZFP36 undergoes oxidative modification as a target of H2O2 in the presence of ABA, specifically at Cys32. Employing quantitative detection and fluorescence assays, we observed that ZFP36 oxidation enhances the expression and activity of genes encoding protective antioxidant enzymes. Moreover, our investigation into the thioredoxin (Trx) and glutaredoxin (Grx) families revealed that OsTrxh1 facilitates the reduction of oxidized ZFP36. Genetic evidence indicates that ZFP36 positively influences rice resilience to oxidative and water stress, while OsTrxh1 exerts an opposing effect. These insights reveal a distinctive pathway for plant cells to perceive ABA-induced H2O2 signaling, advance our comprehension of H2O2 signaling dynamics, and ABA-related plant responses, and lay a vital groundwork for enhancing crop stress tolerance.

Persulfidome of Sweet Pepper Fruits during Ripening: The Case Study of Leucine Aminopeptidase That Is Positively Modulated by H2S.

Protein persulfidation is a thiol-based oxidative posttranslational modification (oxiPTM) that involves the modification of susceptible cysteine thiol groups present in peptides and proteins through hydrogen sulfide (H2S), thus affecting their function. Using sweet pepper (Capsicum annuum L.) fruits as a model material at different stages of ripening (immature green and ripe red), endogenous persulfidated proteins (persulfidome) were labeled using the dimedone switch method and identified using liquid chromatography and mass spectrometry analysis (LC-MS/MS). A total of 891 persulfidated proteins were found in pepper fruits, either immature green or ripe red. Among these, 370 proteins were exclusively present in green pepper, 237 proteins were exclusively present in red pepper, and 284 proteins were shared between both stages of ripening. A comparative analysis of the pepper persulfidome with that described in Arabidopsis leaves allowed the identification of 25% of common proteins. Among these proteins, glutathione reductase (GR) and leucine aminopeptidase (LAP) were selected to evaluate the effect of persulfidation using an in vitro approach. GR activity was unaffected, whereas LAP activity increased by 3-fold after persulfidation. Furthermore, this effect was reverted through treatment with dithiothreitol (DTT). To our knowledge, this is the first persulfidome described in fruits, which opens new avenues to study H2S metabolism. Additionally, the results obtained lead us to hypothesize that LAP could be involved in glutathione (GSH) recycling in pepper fruits.

Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Protects against Binge Alcohol-Mediated Gut and Brain Injury.

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and Aldh2-knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female Aldh2-KO and C57BL/6J wild-type (WT) mice were gavaged with binge alcohol (4 g/kg/dose, three doses) or dextrose (control) at 12 h intervals. Tissues and sera were collected 1 h after the last ethanol dose and evaluated by histological and biochemical analyses of the gut and hippocampus and their extracts. For the mechanistic study, mouse neuroblast Neuro2A cells were exposed to ethanol with or without an Aldh2 inhibitor (Daidzin). Binge alcohol decreased intestinal tight/adherens junction proteins but increased oxidative stress-mediated post-translational modifications (PTMs) and enterocyte apoptosis, leading to elevated gut leakiness and endotoxemia in Aldh2-KO mice compared to corresponding WT mice. Alcohol-exposed Aldh2-KO mice also showed higher levels of hippocampal brain injury, oxidative stress-related PTMs, and neuronal apoptosis than the WT mice. Additionally, alcohol exposure reduced Neuro2A cell viability with elevated oxidative stress-related PTMs and apoptosis, all of which were exacerbated by Aldh2 inhibition. Our results show for the first time that ALDH2 plays a protective role in binge alcohol-induced brain injury partly through the gut-brain axis, suggesting that ALDH2 is a potential target for attenuating alcohol-induced tissue injury.

The association of protein-bound methionine sulfoxide with proteomic basis for aging in beech seeds

BackgroundEuropean beech (Fagus sylvatica L.) trees produce seeds irregularly; therefore, it is necessary to store beech seeds for forestation. Despite the acquisition of desiccation tolerance during development, beech seeds are classified as intermediate because they lose viability during long-term storage faster than typical orthodox seeds. In this study, beech seeds stored for short (3 years) or long (20 years) periods under optimal conditions and displaying 92 and 30% germination capacity, respectively, were compared.ResultsAged seeds displayed increased membrane damage, manifested as electrolyte leakage and lipid peroxidation levels. Analyses have been based on embryonic axes, which contained higher levels of reactive oxygen species (ROS) and higher levels of protein-bound methionine sulfoxide (MetO) in aged seeds. Using label-free quantitative proteomics, 3,949 proteins were identified, of which 2,442 were reliably quantified pointing to 24 more abundant proteins and 35 less abundant proteins in beech seeds under long-term storage conditions. Functional analyses based on gene ontology annotations revealed that nucleic acid binding activity (molecular function), ribosome organization or biogenesis and transmembrane transport (cellular processes), translational proteins (protein class) and membranous anatomical entities (cellular compartment) were affected in aged seeds. To verify whether MetO, the oxidative posttranslational modification of proteins that can be reversed via the action of methionine sulfoxide reductase (Msr) enzymes, is involved in the aging of beech seeds, we identified and quantified 226 MetO-containing proteins, among which 9 and 19 exhibited significantly up- and downregulated MetO levels, respectively, in beech seeds under long-term storage conditions. Several Msr isoforms were identified and recognized as MsrA1-like, MsrA4, MsrB5 and MsrB5-like in beech seeds. Only MsrA1-like displayed decreased abundance in aged seeds.ConclusionsWe demonstrated that the loss of membrane integrity reflected in the elevated abundance of membrane proteins had a higher impact on seed aging progress than the MetO/Msr system. Proteome analyses enabled us to propose protein Sec61 and glyceraldehyde-3-phosphate dehydrogenase as potential longevity modulators in beech seeds.

Valproic Acid Causes Redox-Regulated Post-Translational Protein Modifications That Are Dependent upon P19 Cellular Differentiation States.

Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted. We hypothesize that VPA causes redox-sensitive post-translational protein modifications that are dependent upon cellular differentiation states. Undifferentiated P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, prior to VPA exposure. Undifferentiated cells treated with VPA alone exhibited an oxidized glutathione redox couple and increased overall protein oxidation, whereas differentiated neurons were protected from protein oxidation via increased S-glutathionylation. Pretreatment with D3T prevented the effects of VPA exposure in undifferentiated cells. Taken together, our findings support redox-sensitive post-translational protein alterations in undifferentiated cells as a mechanism of VPA-induced developmental toxicity and propose NRF2 activation as a means to preserve proper neurogenesis.

NADPH oxidase-mediated sulfenylation of cysteine derivatives regulates plant immunity.

Reactive oxygen species (ROS) are rapidly generated during plant immune responses by respiratory burst oxidase homolog (RBOH), which is a plasma membrane-localized NADPH oxidase. Although regulatory mechanisms of RBOH activity have been well documented, the ROS-mediated downstream signaling is unclear. We here demonstrated that ROS sensor proteins play a central role in ROS signaling via oxidative post-translational modification of cysteine residues, sulfenylation. To detect protein sulfenylation, we used dimedone, which specifically and irreversibly binds to sulfenylated proteins. The sulfenylated proteins were labeled by dimedone in Nicotiana benthamiana leaves, and the conjugates were detected by immunoblot analyses. In addition, a reductant dissociated H2O2-induced conjugates, suggesting that cysteine persulfide and/or polysulfides are involved in sulfenylation. These sulfenylated proteins were continuously increased during both pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in a RBOH-dependent manner. Pharmacological inhibition of ROS sensor proteins by dimedone perturbated cell death, ROS accumulation induced by INF1 and MEK2DD, and defense against fungal pathogens. On the other hand, Rpi-blb2-mediated ETI responses were enhanced by dimedone. These results suggest that the sulfenylation of cysteine and its derivatives in various ROS sensor proteins are important events downstream of the RBOH-dependent ROS burst to regulate plant immune responses.

Mitochondrial remodeling underlying age-induced skeletal muscle wasting: let’s talk about sex

Sarcopenia is associated with reduced quality of life and premature mortality. The sex disparities in the processes underlying sarcopenia pathogenesis, which include mitochondrial dysfunction, are ill-understood and can be decisive for the optimization of sarcopenia-related interventions. To improve the knowledge regarding the sex differences in skeletal muscle aging, the gastrocnemius muscle of young and old female and male rats was analyzed with a focus on mitochondrial remodeling through the proteome profiling of mitochondria-enriched fractions. To the best of our knowledge, this is the first study analyzing sex differences in skeletal muscle mitochondrial proteome remodeling. Data demonstrated that age induced skeletal muscle atrophy and fibrosis in both sexes. In females, however, this adverse skeletal muscle remodeling was more accentuated than in males and might be attributed to an age-related reduction of 17beta-estradiol signaling through its estrogen receptor alpha located in mitochondria. The females-specific mitochondrial remodeling encompassed increased abundance of proteins involved in fatty acid oxidation, decreased abundance of the complexes subunits, and enhanced proneness to oxidative posttranslational modifications. This conceivable accretion of damaged mitochondria in old females might be ascribed to low levels of Parkin, a key mediator of mitophagy. Despite skeletal muscle atrophy and fibrosis, males maintained their testosterone levels throughout aging, as well as their androgen receptor content, and the age-induced mitochondrial remodeling was limited to increased abundance of pyruvate dehydrogenase E1 component subunit beta and electron transfer flavoprotein subunit beta. Herein, for the first time, it was demonstrated that age affects more severely the skeletal muscle mitochondrial proteome of females, reinforcing the necessity of sex-personalized approaches towards sarcopenia management, and the inevitability of the assessment of mitochondrion-related therapeutics.

Ageing-dependent thiol oxidation reveals early oxidation of proteins with core proteostasis functions.

Oxidative post-translational modifications of protein thiols are well recognized as a readily occurring alteration of proteins, which can modify their function and thus control cellular processes. The development of techniques enabling the site-specific assessment of protein thiol oxidation on a proteome-wide scale significantly expanded the number of known oxidation-sensitive protein thiols. However, lacking behind are large-scale data on the redox state of proteins during ageing, a physiological process accompanied by increased levels of endogenous oxidants. Here, we present the landscape of protein thiol oxidation in chronologically aged wild-type Saccharomyces cerevisiae in a time-dependent manner. Our data determine early-oxidation targets in key biological processes governing the de novo production of proteins, protein folding, and degradation, and indicate a hierarchy of cellular responses affected by a reversible redox modification. Comparison with existing datasets in yeast, nematode, fruit fly, and mouse reveals the evolutionary conservation of these oxidation targets. To facilitate accessibility, we integrated the cross-species comparison into the newly developed OxiAge Database.

Redox regulation of chromatin remodelling in plants.

Changes in the cellular redox balance that occur during plant responses to unfavourable environmental conditions significantly affect a myriad of redox-sensitive processes, including those that impact on the epigenetic state of the chromatin. Various epigenetic factors, like histone modifying enzymes, chromatin remodelers, and DNA methyltransferases can be targeted by oxidative posttranslational modifications. As their combined action affects the epigenetic regulation of gene expression, they form an integral part of plant responses to (a)biotic stress. Epigenetic changes triggered by unfavourable environmental conditions are intrinsically linked with primary metabolism that supplies intermediates and donors, such acetyl-CoA and S-adenosyl-methionine, that are critical for the epigenetic decoration of histones and DNA. Here, we review the recent advances in our understanding of redox regulation of chromatin remodelling, dynamics of epigenetic marks, and the interplay between epigenetic control of gene expression, redox signalling and primary metabolism within an (a)biotic stress context.