Redox Changes Research Articles

Redox Changes during the Past 100 ka in the Deeper Eastern Arabian Sea: A Study Based on Trace Elements and Multivariate Statistical Analysis

The temporal distribution of trace elements in a sediment core (SK117/GC-08) indicates minor changes in oxygenation during the last 100 kilo years in the bottom waters of the deeper eastern Arabian Sea. The high values of Mn, Co, Cu, Mn/Al, Co/Al, Cu/Al, V/Cr, and V/(V + Ni) in the sediments during interglacials and interstitials collectively indicate oxic conditions during warm periods. The high values of Cr, Ni, V, Mo, Cr/Al, Ni/Al, and Ni/Co in sediments during glacials and stadials collectively indicate dysoxic to suboxic conditions during the colder last glacial maximum and during the entire marine isotope stage two. The bottom waters have never experienced anoxic conditions. Multivariate statistics showed the attribution of the trace elements in two factors: cluster 1 (Co, Cu, Mn) was enriched during oxic conditions and cluster 2 (Cr, Mo, Ni, V) was enriched during dysoxic to suboxic conditions. Oxygenation conditions are mainly driven by variations in monsoon-controlled surface water productivity and changes in the flux of circumpolar deep water. The dysoxic to suboxic bottom water conditions developed at the core location during colder climates are very well synchronised with an increased organic matter flux. The main factor that controls the accumulation of the organic-rich sediments in the eastern Arabian Sea during a glacial is the increase in the supply of organic matter from increased primary productivity in the surface waters, controlled by winter monsoon winds, and localized convective mixing. During warmer interglacials and interstadials, the core location has remained well ventilated.

Polystyrene Microplastics of Varying Sizes and Shapes Induce Distinct Redox and Mitochondrial Stress Responses in a Caco-2 Monolayer.

Currently, we lack crucial knowledge on how the physicochemical properties of particles affect cellular health, resulting in an important gap in our understanding of the human toxicity of microplastics (MPs). Our aim was to evaluate the impact of the size and the shape of MPs on uptake and the intracellular effects in a human epithelial colorectal adenocarcinoma (Caco-2) cell line. Spherical (200 nm and 2 µm) and fibre-/fragment-shaped (8.9 ± 10.1 µm by 1.14 ± 0.97 µm) polystyrene microplastics (PS-MPs) were used to study their uptake and the potential to induce redox and mitochondrial stress responses after 24 h of exposure. We demonstrated the cellular uptake of both spherical and fibre-/fragment-shaped MPs in a size-dependent manner. In response to 2 µm spheres, we observed differential expressions of redox-related genes, including HMOX1, CAT, and GPX1. All PS-MPs decreased the intracellular H2O2 levels, which can be attributed to mitochondrial stress responses, such as increased mitochondrial DNA content, footprint, and morphology. Altogether, we demonstrated uptakes and changes in redox and mitochondrial parameters for all PS-MPs, with the 200 nm spheres showing the most profound effects. This suggests that the induction of defensive responses in Caco-2 cells mainly correlates with the number of particles taken up.

Cadmium isotope evidence deciphers enhanced marine productivity during the middle Mesoproterozoic (the Xiamaling formation, North China)

The interval between 1800 and 800 Ma has long been regarded as “boring billion” which lacks major geologic events in marine sediments. Recent studies, however, showed that multiple ocean-atmospheric oxygenations, together with the evolution of eukaryotes occurred in this period. In North China, the ca. 1400 Ma Xiamaling Formation has been reported as a well-preserved sedimentary succession that faithfully records the primary information of multi-geochemical signatures. Iron speciation, trace element, and organic geochemical analyses, together with biomarker and δ15N measurements recognized an ocean with nitrogen limitation, dynamic oceanic chemocline, and the presence of significant populations of both red and green algae from the Xiamaling Formation black shales. However, the precise paleo-productivity of the Xiamaling Formation still remains poorly understood. This study reports analytical results of Cadmium (Cd) isotopes (δ114Cd) from the Xiamaling Formation, which is subdivided into Units 1–5 in a descending order in the Xiahuayuan borehole section of the North China Craton. The newly obtained δ114Cd values, together with other previously published geochemical data are employed to evaluate nutrient utilization by phytoplankton and primary productivity in the 1.4 Ga ocean of North China. The δ114Cd values show a positive excursion from the lower Unit 3 to upper part of Unit 1 in the studied section. Unit 3 yields the lightest δ114Cd value. Integrating the previously published major and trace elements, organic carbon isotopes, total organic carbon (TOC) concentrations, nitrogen isotopes, iron speciation, and biomarkers, we suggest that the non-euxinic condition and lowest nutrient utilization rate may account for the light isotope compositions in Unit 3. Increase in δ114Cd from Unit 3 to lower Unit 2 is interpreted to be triggered by the elevated nutrient utilization rate and paleo-productivity. The pronounced increase in δ114Cd from the lower Unit 2 to upper Unit 2 may be due to the redox change from non-euxinic to euxinic conditions, coupled with an increasing nutrient utilization rate. Although nutrient utilization rate increased from Unit 3 to Unit 2, the consumption of nutrients in the ocean was still likely incomplete, which therefore slowed down the evolution of phytoplanktons in the 1.4 Ga ocean in the North China Craton.

Redox Modulation of Mitochondrial Proteins in the Neurotoxicant Models of Parkinson's Disease.

Significance: Mitochondrial proteins regulate the oxidative phosphorylation, cellular metabolism, and free radical generation. Redox modulation alters the mitochondrial proteins and instigates the damage to dopaminergic neurons. Toxicants contribute to Parkinson's disease (PD) pathogenesis in conjunction with aging and genetic factors. While oxidative modulation of a number of mitochondrial proteins is linked to xenobiotic exposure, little is known about its role in the toxicant-induced PD. Understanding the role of redox modulation of mitochondrial proteins in complex cellular events leading to neurodegeneration is highly relevant. Recent Advances: Many toxicants are shown to inhibit complex I or III and elicit free radical production that alters the redox status of mitochondrial proteins. Implication of redox modulation of the mitochondrial proteins makes them a target to comprehend the underlying mechanism of toxicant-induced PD. Critical Issues: Owing to multifactorial etiology, exploration of onset and progression and treatment outcomes needs a comprehensive approach. The article explains about a few mitochondrial proteins that undergo redox changes along with the promising strategies, which help to alleviate the toxicant-induced redox imbalance leading to neurodegeneration. Future Directions: Although mitochondrial proteins are linked to PD, their role in toxicant-induced parkinsonism is not yet completely known. Preservation of antioxidant defense machinery could alleviate the redox modulation of mitochondrial proteins. Targeted antioxidant delivery, use of metal chelators, and activation of nuclear factor erythroid 2-related factor 2, and combinational therapy that encounters multiple free radicals, could ameliorate the redox modulation of mitochondrial proteins and thereby PD progression.

No Furongian Biodiversity Gap: Evidence from South China

The middle–late Cambrian is a crucial transition interval linking the Cambrian Explosion (CE) and the Great Ordovician Biodiversification Event (GOBE). Previous studies have indicated the Furongian Biodiversity Gap with significantly lower richness and indistinct changes during this time interval. However, in addition to newly discovered deposits and Konservat-Lagerstätten (i.e., Guole Konservat-Lagerstätte in South China), and well-preserved continuous stratigraphic successions, the detailed richness pattern of this interval has emerged, filling the gap between the CE and the GOBE. The high-resolution richness curve of marine invertebrates in South China based on Constrained Optimization analysis revealed several biodiversity events, including three extinctions, two radiations, and one fluctuation interval. The first biotic crisis, the Guzhangian–Paibian extinction, accounted for a 45.0% richness loss and coincided with the global Marjuman extinction event previously identified in the Laurentian trilobite and brachiopod records. The second extinction, the Jiangshanian extinction, resulting in a 55.2% richness loss, can be correlated to the Steptoean–Sunwaptan biomere extinction in Laurentia. Finally, a third extinction mainly affecting cephalopods and conodonts occurred near the Cambrian/Ordovician boundary in South China, immediately followed by the GOBE, a rapid, extraordinary biodiversity increase in the Early and Middle Ordovician. Two radiation intervals have been recognised in the middle–late Drumian and the middle Paibian, respectively, before the first two extinctions. A long-term richness fluctuation started from the latest Jiangshanian until the Cambrian/Ordovician boundary. Some of the events in South China can be identified in other continents, suggesting a global pattern and mechanism. We further discussed the possible relationships between these biotic and environmental changes. The combined Fe speciation change results showed that the species richness seemed to follow the oceanic redox changes. Thus, there is no significant biodiversity gap but marked fluctuations in marine life associated with environmental volatility between the CE and the GOBE in South China.

Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.

The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.

Redox conditions and ecological resilience during Oceanic Anoxic Event 2 in the Western Interior Seaway

Oceanic Anoxic Events (OAEs) are important geological events that may be analogues to future climate-driven deoxygenation of our oceans. Much of the global ocean experienced anoxic conditions during the Cenomanian–Turonian OAE (OAE2; ∼94 Ma), whereas the Western Interior Seaway (WIS) experienced oxygenation at this time. Here, organic geochemical and palynological data generated from Cenomanian–Turonian age sediments from five sites in the WIS are used to investigate changing redox and ecological conditions across differing palaeoenvironments and palaeolatitudes. Heterogeneity across the sites is apparent, but important relationships and trends among oceanographic variables are recognised: 1) Increasing total organic carbon (TOC) and CaCO3 percentages indicate the onset of a sea-level maximum towards the end of OAE2; 2) C28 sterane is shown to be a useful marker for prasinophyte abundance, and concurrent increases in this marker and overall sterane abundance indicate prasinophyte-driven increase in algal productivity in a stratified water column; and 3) sterane ratios can be a more reliable geochemical proxy than redox proxies for assessing the Benthic Oxic Zone. Our redox data do not always follow established trends for the WIS overall, particularly for proximal settings. We therefore surmise that local effects, such as nutrient-driven expansion of the oxygen minimum zone and/or sedimentation-driven anoxia just below the sediment-water interface, have overprinted regional trends.

Extreme Copper Isotope Fractionation Driven by Redox Oscillation During Gleysols Weathering in Mun River Basin, Northeast Thailand

AbstractCopper (Cu) isotopes are utilized to track Cu geochemical cycling in weathered gleysols of tropical zones. A significant isotope fractionation of Cu in these soils is primarily redox‐controlled; however, it is rarely reported how the frequency of redox fluctuations affects the soil Cu isotope signature. This study investigated the variations of Cu content and isotope fractionation in two low‐humic gleysol profiles (S1 and S2) from a dry tropical savanna zone. Owing to redox oscillation during weathering, δ65Cu values in profile S2 showed a stronger positive correlation with the mafic index of alteration of reducing environment than S1, and isotopically light Cu is more retained in the Zone II of profile S2 than S1. As the frequency of redox fluctuation increased, the retained stable Cu(I) species and light Cu isotopes increased in the residual soils through re‐adsorption or re‐precipitation by iron oxyhydroxide (i.e., ferrihydrite). Importantly, an Mn‐enriched zone was formed after reduction events in profile S2, and found to be enriched in light Cu isotopes. The heavier Cu fraction might be lost by adsorption on Fe oxyhydroxides in the Mn‐rich zone, while the relatively light Cu might be retained through adsorption on Mn oxyhydroxides. Additionally, a significant Soil Organic Carbon (SOC) contribution to Cu was found due to the high δ65Cu‐SOC correlation (R2 = 0.80) in S1 (depth <1 m). Therefore, our study shows that the Cu isotope signature can respond to redox changes in the terrestrial ecosystem, and these Cu isotope signatures may have significant implications for assessing soil ecological vulnerability under future climate change scenarios.

Branched-chain amino acids alter cellular redox to induce lipid oxidation and reduce de novo lipogenesis in the liver.

Metabolic and molecular interactions between branched-chain amino acid (BCAA) and lipid metabolism are evident in insulin-resistant tissues. However, it remains unclear whether insulin resistance is a prerequisite for these relationships and whether BCAAs or their metabolic intermediates can modulate hepatic lipid oxidation and synthesis. We hypothesized that BCAAs can alter hepatic oxidative function and de novo lipogenesis, independent of them being anaplerotic substrates for the mitochondria. Mice (C57BL/6NJ) were reared on a low-fat (LF), LF diet plus 1.5X BCAAs (LB), high-fat (HF) or HF diet plus 1.5X BCAAs (HB) for 12 wk. Hepatic metabolism was profiled utilizing stable isotopes coupled to mass spectrometry and nuclear magnetic resonance, together with fed-to-fasted changes in gene and protein expression. A greater induction of lipid oxidation and ketogenesis on fasting was evident in the BCAA-supplemented, insulin-sensitive livers from LB mice, whereas their rates of hepatic de novo lipogenesis remained lower than their LF counterparts. Onset of insulin resistance in HF and HB mice livers blunted these responses. Whole body turnover of BCAAs and their ketoacids, their serum concentrations, and the ketogenic flux from BCAA catabolism, all remained similar between fasted LF and LB mice. This suggested that the impact of BCAAs on lipid metabolism can occur independent of them or their degradation products fueling anaplerosis through the liver mitochondria. Furthermore, the greater induction of lipid oxidation in the LB livers accompanied higher mitochondrial NADH/NAD+ ratio and higher fed-to-fasting phosphorylation of AMPKα and ACC. Taken together, our results provide evidence that BCAA supplementation, under conditions of insulin sensitivity, improved the feeding-to-fasting induction of hepatic lipid oxidation through changes in cellular redox, thus providing a favorable biochemical environment for flux through β-oxidation and lower de novo lipogenesis.NEW & NOTEWORTHY Branched-chain amino acids (BCAAs) have been shown to modulate lipid metabolic networks in various tissues, especially during insulin resistance. In this study we show that the dietary supplementation of BCAAs to normal, insulin-sensitive mice resulted in higher mitochondrial NADH:NAD+ ratios and AMPK activation in the liver. This change in the cellular redox status provided an optimal metabolic milieu to increase fatty acid oxidation while keeping the rates of de novo lipogenesis lower in the BCAA-supplemented mice livers.

Nuclear magnetic resonance at the laboratory and field scale as a tool for detecting redox fronts in aquifers

Surface nuclear magnetic resonance (NMR) provides information not only on the lithology and water transport characteristics of aquifer systems but also on the state of iron mineralization within the pore space. This feature makes surface NMR a potential tool for the observation of changing redox conditions in the aquifer, which control the type and oxidation state of iron minerals and, relatedly, the buffering or release of pollutants that may pose a threat to drinking water resources. Our study aims on testing this potential and focuses on pyrite contained in the matrix of a sandy aquifer that serves as a natural denitrification buffer in a drinking water catchment area with intensive agricultural use. We observe a significant change in the surface-NMR relaxation times related to the pyrite content in the subsurface, which is most obvious at the transition from the pyrite-free oxic zone and the pyrite-bearing reducing zone. Complementary laboratory experiments using core material from the study site, including laboratory NMR and geochemical analyses, verify that the influence of pyrite content predominates the NMR relaxation behavior rather than pore size, porosity, or carbon content. The mean relaxation times measured in the sediment without pyrite exceed those with pyrite by approximately 20%–100%. We conclude that surface NMR can serve as a capable tool to locate and monitor the pyrite-based denitrification buffer. However, for general applicability within the given framework, more research is needed to address the natural ambiguity among iron content, its redox state and speciation, and pore size.

Global ocean redox changes before and during the Toarcian Oceanic Anoxic Event

Mesozoic oceanic anoxic events are recognized as widespread deposits of marine organic-rich mudrocks temporally associated with mass extinctions and large igneous province emplacement. The Toarcian Oceanic Anoxic Event is one example during which expanded ocean anoxia is hypothesized in response to environmental perturbations associated with emplacement of the Karoo–Ferrar igneous province. However, the global extent of total seafloor anoxia and the relative extent of euxinic (anoxic and sulfide-rich) and non-euxinic anoxic conditions during the Toarcian Oceanic Anoxic Event are poorly constrained. Here we present estimates of the global total anoxic and euxinic seafloor areas before and during the Toarcian Oceanic Anoxic Event based on rhenium and molybdenum enrichments, respectively, in organic-rich mudrocks of the Fernie Formation (British Columbia, Canada). We find that mass balance models depict an expansion of up to ~7% total seafloor anoxia, which was dominated by euxinia, at the onset of the Toarcian Oceanic Anoxic Event, followed by a contraction before the end of the event. The global ocean redox trends revealed by the rhenium data mirrors the collapse and recovery patterns of global ammonite and foraminiferal biodiversity.

Glutathione Transferases are Involved in Salicylic Acid-Induced Transcriptional Reprogramming

Salicylic acid (SA) plays a crucial role not only in defence against pathogen attacks, but also in abiotic stress responses. Recently, some key steps of SA signalling outlined the importance of redox state-dependent processes. This study explores the role of glutathione transferases (GSTs) in the transcriptional reprogramming of redox status-related genes in seven-day-old wild type and Atgst mutant Arabidopsis thaliana plants. The timing of redox changes, detected by the redox-sensitive green fluorescent protein (roGFP2), differed in wild type roots treated with 10 μM or 100 μM SA. Our results verified how the applied SA concentrations had different effect on the expression of oxidative stress- and redox-related genes, among them on the expression of AtGSTF8 and AtGSTU19 genes. Lower vitality and less negative EGSH values were specific characteristics of the Atgst mutants compared to the wild type plants throughout the experiment. Changes in the redox potential were only modest in the mutants after SA treatments. A slightly modified gene expression pattern was observed in control conditions and after 1 h of SA treatments in Atgst mutants compared to Col-0 roots. These data originating from the whole roots provide indirect evidence for the role of the investigated AtGSTF8 and AtGSTU19 isoenzymes in the transduction of the redox signal. Our results demonstrate that the investigated Arabidopsis GSTs have a role in maintaining the levels of reactive oxygen species- and redox homeostasis and are involved in transcriptional reprogramming in the roots.

The adaptive response to alternative carbon sources in the pathogen Candida albicans involves a remodeling of thiol- and glutathione-dependent redox status.

Candida albicans is an opportunist pathogen responsible for a large spectrum of infections, from superficial mycosis to systemic diseases known as candidiasis. During infection in vivo, Candida albicans must adapt to host microenvironments and this adaptive response is crucial for the survival of this organism, as it facilitates the effective assimilation of alternative carbon sources others than glucose. We performed a global proteomic analysis on the global changes in protein abundance in response to changes in micronutrient levels, and, in parallel, explored changes in the intracellular redox and metabolic status of the cells. We show here that each of the carbon sources considered - glucose, acetate and lactate - induces a unique pattern of response in C. albicans cells, and that some conditions trigger an original and specific adaptive response involving the adaptation of metabolic pathways, but also a complete remodeling of thiol-dependent antioxidant defenses. Protein S-thiolation and the overproduction of reduced glutathione are two components of the response to high glucose concentration. In the presence of acetate, glutathione-dependent oxidative stress occurs, reduced thiol groups bind to proteins, and glutathione is exported out of the cells, these changes probably being triggered by an increase in glutathione-S-transferases. Overall, our results suggest that the role of cellular redox status regulation and defenses against oxidative stress, including the thiol- and glutathione-dependent response, in the adaptive response of C. albicans to alternative carbon sources should be reconsidered.

Dynamic oceanic redox conditions across the late Cambrian SPICE event constrained by molybdenum and uranium isotopes

The Steptoean Positive Carbon Isotope Excursion Event (SPICE) represents one of the largest carbon cycle perturbations in the Cambrian, which coincided with climatic changes and dramatic extinction of shallow-shelf faunas. This carbon perturbation has been linked to a global expansion of marine euxinia (SPICE-OAE), but the precise timing, duration and extent of changing redox conditions across the SPICE event, as well as its influences on the coeval biotic evolution, remain unclear. Here, we report paired δ98Mo–δ238U data across this event, constrained by a radioisotopically anchored astrochronology, based on Alum Shale samples from the Albjära-1 and Billegrav-2 drill-cores in Scandinavia. The δ98Mo profiles are largely invariant around 1.08±0.21‰ with short-term fluctuations parallelling changes in pyritization of iron, possibly as a result of locally varying [H2S]aq in the water column and/or fluctuating reactive iron delivery. The bottom water is interpreted to have been primarily anoxic, but with frequent local variations between oxic and sulfidic conditions in a moderately restricted basin. A novel analytic method based on variation of Mo concentrations at millimeter scale stratigraphic resolution was applied to distinguish between local and global redox signatures, revealing that cyclic redox changes are recorded in the Alum Shale sea with periods of ∼0.3 Myr, ∼0.9 Myr and ∼0.15 Myr before, during and after the SPICE-OAE, respectively. Stratigraphic profiles of Mo, U, Mo/TOC ratios and δ238U in the two cores show comparable trends, facilitating recognition of three chemically distinct stages across the SPICE event: 1) global expansion of marine euxinia (SPICE-OAE; 497.9–496.6 Ma), 2) global contraction of euxinia accompanied by enhanced carbonate weathering inputs (496.6–495.8 Ma) and 3) general global oxygenation (495.8–494.4 Ma). The first in situ correlation between the onset of the SPICE-OAE and the end-Miaolingian extinctions in Baltica corroborates that expansive anoxic and sulfidic water masses likely contributed to the biotic crisis. The time gap between the start of the extinction and the appearance of the new fauna in Baltoscandia is estimated to be ∼600 kyr.

Design and engineering switchable artificial metalloproteins.

Life requires stable temperatures and pH to sustain the complex biological machinery within the cell. To accommodate the strict environmental conditions for life to proceed, biological processes are often regulated by conformational changes. The approaches used in our research combine conformational flexibility of periplasmic binding proteins and the knowledge of the well-established molecularly rigid artificial metalloproteins to probe the role and mechanisms of conformational regulation. We are creating switchable artificial metalloproteins (swArMs) that undergo conformational changes upon effector binding at a site allosteric to the installed metallocofactor. Specifically, we have bioconjugated a cobalt complex via cysteine ligation within the glutamine binding protein and observed faster bond breaking upon binding to the allosteric effector, glutamine. We are also working to develop reversible swArMs. To this end, we are characterizing and engineering a periplasmic binding protein (PqqT) that natively binds pyrroloquinoline quinone (PQQ). Our aim is to drive redox changes in PQQ that in turn, drive conformational changes in PqqT. Structural characterization of this association complex through x-ray diffraction is underway that will inform our ability to convert this protein into an artificial methanol dehydrogenase. The described research lays groundwork for studying how protein dynamics influence function, with the goal of understanding what makes metalloproteins in nature so optimal for the chemistry they perform.

Protective effect of vitamin E against plumbagin-induced liver injury and oxidative stress: biochemical, redox, and mitochondrial permeability changes

Protective effect of vitamin E against plumbagin-induced liver injury and oxidative stress: biochemical, redox, and mitochondrial permeability changes

Parkin coregulates glutathione metabolism in adult mammalian brain

We recently discovered that the expression of PRKN, a young-onset Parkinson disease-linked gene, confers redox homeostasis. To further examine the protective effects of parkin in an oxidative stress model, we first combined the loss of prkn with Sod2 haploinsufficiency in mice. Although adult prkn−/−//Sod2± animals did not develop dopamine cell loss in the S. nigra, they had more reactive oxidative species and a higher concentration of carbonylated proteins in the brain; bi-genic mice also showed a trend for more nitrotyrosinated proteins. Because these redox changes were seen in the cytosol rather than mitochondria, we next explored the thiol network in the context of PRKN expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, PRKN-linked human cortex and several cell models. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione reductase activity; it also correlated with altered activities of redox-sensitive enzymes in mitochondria isolated from mouse brain (e.g., aconitase-2; creatine kinase). Intriguingly, human parkin itself showed glutathione-recycling activity in vitro and in cells: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S-glutathionylated by the other (GSSG + P-SH to GSH + P-S-SG), including at cysteines 59, 95 and 377. Moreover, parkin’s S-glutathionylation was reversible by glutaredoxin activity. In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, including by parkin’s participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin’s impact on redox homeostasis in the cytosol can affect enzyme activities elsewhere, such as in mitochondria. We posit that antioxidant functions of parkin may explain many of its previously described, protective effects in vertebrates and invertebrates that are unrelated to E3 ligase activity.

Schizophrenia as metabolic disease. What are the causes?

Schizophrenia (SZ) is a devastating neurodevelopmental disease with an accelerated ageing feature. The criteria of metabolic disease firmly fit with those of schizophrenia. Disturbances in energy and mitochondria are at the core of complex pathology. Genetic and environmental interaction creates changes in redox, inflammation, and apoptosis. All the factors behind schizophrenia interact in a cycle where it is difficult to discriminate between the cause and the effect. New technology and advances in the multi-dispensary fields could break this cycle in the future.

Mitochondrial and Redox Changes in Periodontitis and Type 2 Diabetes Human Blood Mononuclear Cells.

Periodontitis (PDT) and type 2 diabetes (T2D) have demonstrated a bidirectional relationship and imbalanced oxidative stress linked to mitochondrial dysfunction. Therefore, we investigated mitochondrial and redox (de)regulation in peripheral blood mononuclear cells (PBMCs) in comorbid T2D-PDT, compared to PDT, T2D patients, and control individuals. PBMCs were analyzed for mitochondrial respiration, reactive oxygen species, antioxidant proteins, and expression of Nrf2-target genes. PDT and T2D-PDT patients exhibited altered periodontal clinical markers, while T2D and T2D-PDT patients displayed increased blood HbA1c. Decreased oxygen consumption and ATP production were observed in the PDT patient's PBMCs. PDT and T2D-PDT PBMCs also evidenced increased H2O2 levels and reduced catalase levels (also detected in T2D patients), whereas a compromised glutathione cycle was observed in T2D-PDT patients. PBMCs from both T2D or T2D-PDT patients showed increased Nrf2 protein levels, enhanced GCL activity and GCL-catalytic subunit protein levels, and maintained GCLc, GST, and HO-1 mRNA levels. In contrast, the expressions of Nrf2-target genes were significantly diminished in the PDT patient's PBMCs. Decreased SOD1 and GST mRNA levels were also observed in CD3+CD8+-lymphocytes derived from PDT and T2D-PDT patients. In conclusion, PBMCs from T2D-PDT patients showed major redox changes, while mononuclear cells from PDT patients showed mitochondrial deregulation and reduced expression of Nrf2-target genes.

Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism.

No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood, and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following carbohydrate nutrition, injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle adaptation, and brain executive function, growth and development, and a treatment for inflammatory conditions. Lactate also works with many other mechanisms and factors in controlling cardiac output and pulmonary ventilation during exercise. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic β-cell membranes is not suppressed, and in carcinogenesis when factors that suppress carcinogenesis are inhibited, whereas factors that promote carcinogenesis are upregulated. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, neurobiology, gut physiology, appetite regulation, nutrition, and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.NEW & NOTEWORTHY Lactate sensing and signaling is a relatively new and rapidly changing field. As a physiological signal lactate works both independently and in concert with other signals. Lactate operates via covalent binding and canonical signaling, redox change, and lactylation of DNA. Lactate can also serve as an element of feedback loops in cardiopulmonary regulation. From conception through aging lactate is not the only a myokine or exerkine, but it certainly deserves consideration as a physiological signal.