Redox Signaling Mechanisms Research Articles

Aging-associated Aberrant Mitochondrial Redox Signaling, Physical Activity, and Sarcopenia.

Aging-related alteration of mitochondrial morphology, impairment in metabolic capacity, bioenergetics, and biogenesis are closely associated with loss of muscle mass and function. Mitochondrial Reactive Oxygen Species (ROS) stimulate muscular redox signaling mechanisms. Bioenergetic integrity of mitochondria and redox signaling dynamics deteriorates in aged skeletal muscle. Mitochondrial bioenergetic impairment leads to excessive ROS levels and induces the generation of defective mitochondria. Higher ROS levels may induce senescence or apoptosis. It is not a resolved issue that mitochondrial dysfunction is either the sole reason or a consequence of muscle loss (or both). However, Increasing evidence emphasizes that dysregulated mitochondrial redox signaling has a central role in age-related muscle loss. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox signaling pathways with the expression of antioxidant genes. As the aberrant redox signaling mechanisms in aging skeletal muscle become clearer, new natural and synthetic Nrf2-modulating substances and integrated daily physical activity alternatives are coming into view for preventing muscle loss in the elderly. A comprehensive understanding of the relationship between redox signaling pathways and age-related sarcopenia can help us to prevent sarcopenia and its frailty effects with an optimized exercise program as an innovative non-pharmacological therapeutic approach. A further aspect is necessary to consider both individualized physical training options and alternative Nrf2 signaling modulators. Ameliorating the redox signaling with physical activity and pharmacological interventions may help to prevent sarcopenia and its frailty effects.

Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease.

Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n=27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.

The Possible Mechanisms of Cu and Zn in the Treatment and Prevention of HIV and COVID-19 Viral Infection.

Due to their unique properties and their potential therapeutic and prophylactic applications, heavy metals have attracted the interest of many researchers, especially during the outbreak of COVID-19. Indeed, zinc (Zn) and copper (Cu) have been widely used during viral infections. Zn has been reported to prevent excessive inflammatory response and cytokine storm, improve the response of the virus to Type I interferon (IFN-1), and enhance the production of IFN-a to counteract the antagonistic effect of SARS-CoV-2 virus protein on IFN. Additionally, Zn has been found to promote the proliferation and differentiation of T and B lymphocytes, thereby improving immune function, inhibiting RNA-dependent RNA polymerase (RdRp) in SARS- CoV-2 reducing the viral replication and stabilizing the cell membrane by preventing the proteolytic processing of viral polyprotein and proteases enzymes. Interestingly, Zn deficiency has been correlated with enhanced SARS-CoV-2 viral entry through interaction between the ACE2 receptor and viral spike protein. Along with zinc, Cu possesses strong virucidal capabilities and is known to be effective at neutralizing a variety of infectious viruses, including the poliovirus, influenza virus, HIV type 1, and other enveloped or nonenveloped, single- or double-stranded DNA and RNA viruses. Cu-related antiviral action has been linked to different pathways. First, it may result in permanent damage to the viral membrane, envelopes, and genetic material of viruses. Second, Cu produces reactive oxygen species to take advantage of the redox signaling mechanism to eradicate the virus. The present review focused on Zn and Cu in the treatment and prevention of viral infection. Moreover, the application of metals such as Cu and gold in nanotechnology for the development of antiviral therapies and vaccines has been also discussed.

The Role of Heat Shock Proteins and Autophagy in Mechanisms Underlying Effects of Sulforaphane on Doxorubicin-Induced Toxicity in HEK293 Cells.

Doxorubicin (DOX) is a cytostatic agent belonging to anthracycline group. Important role in mechanism associated with negative effects of DOX plays an oxidative stress. Heat shock proteins (HSPs) are part of mechanisms initiated in response to stressful stimuli and play an important role in cellular responses to oxidative stress through interaction with components of redox signaling. The present work was aimed to study the role of HSPs and autophagy in mechanisms underlying effects of sulforaphane (SFN), a potential activator of Nrf-2, on doxorubicin-induced toxicity in human kidney HEK293 cells. We investigated effects of SFN and DOX on proteins associated with regulation of heat shock response, redox signaling, and autophagy. Results show that SFN significantly reduced cytotoxic effects of DOX. The positive effects of SFN on DOX-induced changes were associated with up-regulation of Nrf-2 and HSP60 protein levels. In the case of another heat shock protein HSP40, SFN increased its levels when was administered alone but not in conditions when cells were exposed to the effects of DOX. Sulforaphane also reversed negative effects of DOX on activities of superoxide dismutases (SODs) and up-regulation of autophagy markers (LC3A/B-II, Atg5, and Atg12). In conclusion, the changes observed in HSP60 are of particular importance in terms of protecting cells from the effects of DOX. Finding that under conditions where SFN reduced cytotoxic effects of DOX were significantly increased protein levels of both Nrf-2 and HSP60 point to the role of HSP60 in mechanisms of redox signaling underlying effects of SFN on DOX-induced toxicity in HEK293 cells. Moreover, data confirmed an important role of autophagy in effects of SFN on DOX-induced toxicity.

Thiol/Disulfide Homeostasis and Ischemia-Modified Albumin Levels in 61 Patients with Hypercapnia: A Case-Control Study.

BACKGROUND Hypercapnia is abnormally high arterial partial pressure of carbon dioxide (CO₂). CO₂ can affect redox signaling mechanisms, leading to production of oxidative derivatives. Thiol is formed by attaching a sulfhydryl group to a carbon atom. Under oxidative stress, it forms covalent bonds called thiol disulphide bonds. Serum albumin is modified to ischemia-modified albumin (IMA) by exposure to free radicals. This case-control study aimed to evaluate thiol/disulphide homeostasis and IMA levels in 61 patients with hypercapnia. MATERIAL AND METHODS We studied 61 patients with hypercapnia and 61 normocapnic volunteers in the control group, between May 2018 and January 2019; 56 of these patients were diagnosed with chronic obstructive pulmonary disease and 5 of them were diagnosed with obstructive sleep apnea syndrome. Arterial blood samples analyzed by using the Ellman reagent for thiol/disulphide data. A colorometric assay was used for detection of IMA levels. RESULTS Native thiol and total thiol values in the hypercapnic group were significantly lower than in the control group (P=0.024, P=0.006 respectively), as IMA values were significantly higher (P<0.001). There was no statistically significant difference between the hypercapnic and control groups in terms of disulphide, disulphide/native thiol, disulphide/total thiol, and native thiol/total thiol values (P>0.05). CONCLUSIONS In hypercapnic patients, there are changes in thiol/disulphide homeostasis and IMA levels. All significant differences in this study support that changes in thiol disulphide homeostasis and IMA in hypercapnic patients are indicators of oxidative stress.

A dual-channel fluorogenic probe for simultaneous and distinguishable imaging of protein monothiols and vicinal-dithiols in live cells

Protein monothiols (MTs) and vicinal-dithiols (VDTs) are ubiquitous in living systems. Redox states of these protein thiols are mutually coupled and balanced, and their alterations are essential for regulating diverse biological processes in cells. However, there is still a lack of sensing strategies for simultaneous and distinguishable imaging of protein MTs and VDTs in live cells. Here, we report the design and synthesis of a fluorogenic probe bearing two thiol-reactive sites embedded into a viscosity/polarity-dual-sensitive fluorophore, which response to protein MTs and VDTs in two different fluorescence channels. This probe enables us to visualize and analyze protein MTs and protein VDTs in living cell without interference from the high abundant small biothiols such as glutathione. We believe that this work would inspire the development of other fluorogenic probes to protein thiols with more elaborated functions (e.g., targeting to subcellular organelles) and would benefit studies on redox signaling mechanism in live cells and other biological processes involving alteration of protein thiols.

Protein S-glutathionylation and sex dimorphic effects on hydrogen peroxide production by dihydroorotate dehydrogenase in liver mitochondria.

Dihydroorotate dehydrogenase (DHODH) oxidizes dihydroorotate to orotate for pyrimidine biosynthesis, donating electrons to the ubiquinone (UQ) pool of mitochondria. DHODH has a measurable rate for hydrogen peroxide (H2O2) production and thus contributes to cellular changes in redox tone. Protein S-glutathionylation serves as a negative feedback loop for the inhibition of H2O2 by several α-keto acid dehydrogenases and respiratory complexes in mitochondria, as well as ROS sources in liver cytoplasm. Here, we report this redox signaling mechanism also inhibits H2O2 production by DHODH in liver mitochondria isolated from male and female C57BL6N mice. We discovered that low amounts of the glutathionylation catalyst, disulfiram (50-500nM), almost abolished H2O2 production by DHODH in mitochondria from male mice. Similar results were collected with diamide, however, higher doses (1000-5000μM) were required to elicit this effect. Disulfiram and diamide also significantly suppressed H2O2 production by DHODH in female liver mitochondria. However, liver mitochondria from female mice were more resistant to disulfiram or diamide-mediated inhibition of H2O2 genesis when compared to samples from males. Analysis of the impact of disulfiram and diamide on DHODH activity revealed that both compounds inhibited the dehydrogenase directly, however the effect was less in female mice. Additionally, disulfiram and diamide impeded the use of dihydroorotate fueled oxidative phosphorylation in mitochondria from males and females, although samples collected from female rodents displayed more resistance to this inhibition. Taken together, our findings demonstrate H2O2 production by DHODH can be inhibited by glutathionylation and sex can impact this redox modification.

Pro-luciferin probes containing (2-diphenylphosphino)benzoate and 2-thiolo-2-methylpropionate moieties: Synthesis, characterization, and reactivity toward nitroxyl

Multiple studies have shown that the generation of the reactive oxygen and nitrogen species (RONS) can promote a tumor formation via a redox-signaling mechanism. RONS in vivo are usually detected by fluorogenic probes. In this study, we report synthesis of four new firefly luciferin-based probes with two different reactive groups for nitroxyl recognition, either (2-diphenylphosphino)benzoate or 2-thiolo-2-methylpropionate moiety. We have also compared the reactivity and selectivity of these probes relative to nitroxyl, hypochlorous acid and another analytes. All studied probes “turn on” fluorescence in the reaction with nitroxyl due to release of the methyl ester of luciferin, that can be used for the bioluminescence imaging of nitroxyl in luciferase-transfected cells. In the reaction with hypochlorous acid, stable nonfluorescent products are formed. The use of various analytical techniques allowed the determination of the stoichiometry of the reaction between the probes and nitroxyl, and confirmed the structures of the resulting products.

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.

Mechanism of GAPDH Redox Signaling by H2O2 Activation of a Two-Cysteine Switch.

Oxidation of glyceraldehyde−3−phosphate dehydrogenase (GAPDH) by reactive oxygen species such as H2O2 activate pleiotropic signaling pathways is associated with pathophysiological cell fate decisions. Oxidized GAPDH binds chaperone proteins with translocation of the complex to the nucleus and mitochondria initiating autophagy and cellular apoptosis. In this study, we establish the mechanism by which H2O2−oxidized GAPDH subunits undergo a subunit conformational rearrangement. H2O2 oxidizes both the catalytic cysteine and a vicinal cysteine (four residues downstream) to their respective sulfenic acids. A ‘two−cysteine switch’ is activated, whereby the sulfenic acids irreversibly condense to an intrachain thiosulfinic ester resulting in a major metastable subunit conformational rearrangement. All four subunits of the homotetramer are uniformly and independently oxidized by H2O2, and the oxidized homotetramer is stabilized at low temperatures. Over time, subunits unfold forming disulfide−linked aggregates with the catalytic cysteine oxidized to a sulfinic acid, resulting from thiosulfinic ester hydrolysis via the highly reactive thiosulfonic ester intermediate. Molecular Dynamic Simulations provide additional mechanistic insights linking GAPDH subunit oxidation with generating a putative signaling conformer. The low−temperature stability of the H2O2−oxidized subunit conformer provides an operable framework to study mechanisms associated with gain−of−function activities of oxidized GAPDH to identify novel targets for the treatment of neurodegenerative diseases.

Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

Mitochondria are important organelles that act as a primary site to produce reactive oxygen species (ROS). Additionally, mitochondria play a pivotal role in the regulation of Ca2+ signaling, fatty acid oxidation, and ketone synthesis. Dysfunction of these signaling molecules leads to the development of pulmonary hypertension (PH), atherosclerosis, and other vascular diseases. Features of PH include vasoconstriction and pulmonary artery (PA) remodeling, which can result from abnormal proliferation, apoptosis, and migration of PA smooth muscle cells (PASMCs). These responses are mediated by increased Rieske iron–sulfur protein (RISP)-dependent mitochondrial ROS production and increased mitochondrial Ca2+ levels. Mitochondrial ROS and Ca2+ can both synergistically activate nuclear factor κB (NF-κB) to trigger inflammatory responses leading to PH, right ventricular failure, and death. Evidence suggests that increased mitochondrial ROS and Ca2+ signaling leads to abnormal synthesis of ketones, which play a critical role in the development of PH. In this review, we discuss some of the recent findings on the important interactive role and molecular mechanisms of mitochondrial ROS and Ca2+ in the development and progression of PH. We also address the contributions of NF-κB-dependent inflammatory responses and ketone-mediated oxidative stress due to abnormal regulation of mitochondrial ROS and Ca2+ signaling in PH.

Mitochondrial redox regulation and myocardial ischemia-reperfusion injury.

Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and redox signaling in the cellular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by complexes I and III of the electron transport chain (ETC) and by the proton motive force (PMF), consisting of a membrane potential (ΔΨ) and a proton gradient (ΔpH). Several factors control redox status in mitochondria, including ROS, the PMF, oxidative posttranslational modifications (OPTM) of the ETC subunits, SOD2, and cytochrome c heme lyase (HCCS). In the mitochondrial PMF, increased ΔpH-supported backpressure due to diminishing electron transport and chemiosmosis promotes a more reductive mitochondrial physiological setting. OPTM by protein cysteine sulfonation in complex I and complex III has been shown to affect enzymatic catalysis, the proton gradient, redox status, and enzyme-mediated ROS production. Pathological conditions associated with oxidative or nitrosative stress, such as myocardial ischemia and reperfusion (I/R), increase mitochondrial ROS production and redox dysfunction via oxidative injury to complexes I and III, intensely enhancing protein cysteine sulfonation and impairing heme integrity. The physiological conditions of reductive stress induced by gains in SOD2 function normalize I/R-mediated ROS overproduction and redox dysfunction. Further insight into the cellular mechanisms by which HCCS, biogenesis of c-type cytochrome, and OPTM regulate PMF and ROS production in mitochondria will enrich our understanding of redox signal transduction and identify new therapeutic targets for cardiovascular diseases in which oxidative stress perturbs normal redox signaling.

Review: Using isolated mitochondria to investigate mitochondrial hydrogen peroxide metabolism.

Mitochondria are recognized as centrally important to cellular reactive oxygen species (ROS), both as a potential source and due to their substantial antioxidant capacity. While much of the initial ROS formed by mitochondria is superoxide, this is rapidly converted to hydrogen peroxide (H2O2) which more readily crosses membranes making H2O2 important in both redox signalling mechanisms and conditions of oxidative stress. Here I outline our studies on mitochondrial H2O2 metabolism with a focus on some of the challenges and strategies involved with developing an integrated model of mitochondria being intrinsic regulators of H2O2. This view of mitochondria as regulators of H2O2 goes beyond the simpler contention of them being net producers or consumers. Moreover, the integration of both consumption and production can then be tied to a putative mechanism linking energy sensing at the level of the mitochondrial protonmotive force. This mechanism would provide a means of mitochondria communicating their energetic status the extramitochondrial compartment via local H2O2 concentrations. I conclude by explaining how these concepts developed using rodent muscle as a model have high relevance and applicability to comparative studies.

A Compendium on Hypertension: New Advances and Future Impact.

A Compendium on Hypertension: New Advances and Future Impact.

Regulation of redox processes in biological systems with the participation of the Keap1/Nrf2/ARE signaling pathway, biogenic selenium nanoparticles as Nrf2 activators

The article is devoted to the mechanisms of regulation of redox processes in cells, a review of the Keap1 / Nrf2 / ARE redox-sensitive signaling system as a fundamental pathway that plays a key role in maintaining cellular redox homeostasis under stressful, inflammatory, carcinogenic and proapoptotic conditions. The structure of the cysteine-rich repressor protein Keap1, which is responsible for sensory perception of electrophiles and reactive oxygen species, the structure and functions of the transcription factor Nrf2, mechanisms of Nrf2 activation through the Keap1 / Nrf2 / ARE signaling system, which regulates the transcription and expression of cellular cytoprotective and antioxidant proteins, are described. Published data on the specificity of the interaction of the components of this cellular signaling pathway, the mechanisms of Keap1 dependent and independent adaptive response to the action of inductors, the role of biogenic selenium nanoparticles synthesized by green chemistry with the participation of bacteria in these processes are analyzed; features of Nrf2 induction depending on the type of bacteria and the stabilizing shell. It has been shown that biogenic selenium nanoparticles (BNSe), synthesized by different types of bacteria, activate the transcription factor Nrf2 using the Keap1-independent activation pathway through mitogen-protein kinases (MAPK): p38, ERK1 / 2 and AKT-mediated phosphorylation of Nrf2, protect the intestinal epithelial barrier function from the effects of oxidative damage, normalize mitochondrial function. A detailed understanding of thiol-dependent and independent redox signaling mechanisms under physiological and pathological conditions will lead to a deeper understanding of the redox component in human and animal diseases. The use of biogenic nanoselen, synthesized with the participation of various bacterial species, has been demonstrated to activate the Keap1 / Nrf2 / ARE signaling pathway, which may be of practical interest as a therapeutic target for many redox-mediated diseases.

Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease.

Chronic kidney disease (CKD) remains a worldwide public health problem associated with serious complications and increased mortality rates. Accumulating evidence indicates that elevated intracellular levels of reactive oxygen species (ROS) play a major role in the pathogenesis of CKD. Increased intracellular levels of ROS can lead to oxidation of lipids, DNA, and proteins, contributing to cellular damage. On the other hand, ROS are also important secondary messengers in cellular signaling. Consequently, normal kidney cell function relies on the “right” amount of ROS. Mitochondria and NADPH oxidases represent major sources of ROS in the kidney, but renal antioxidant systems, such as superoxide dismutase, catalase, or glutathione peroxidase counterbalance ROS-mediated injury. This review discusses the main sources of ROS and antioxidant systems in the kidney, and redox signaling pathways leading to inflammation and fibrosis, which result in abnormal kidney function and CKD progression. We further discuss the important role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating antioxidant responses, and other mechanisms of redox signaling.

New Insights in the Mechanisms of Impaired Redox Signaling and its Interplay With Inflammation and Immunity in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination and axonal damage and resulting in a range of physical, mental or even psychiatric symptoms. Key role of oxidative stress (OS) in the pathogenesis of MS has been suggested, as indicated by the biochemical analysis of cerebrospinal fluid and blood samples, tissue homogenates, and animal models of multiple sclerosis. OS causes demyelination and neurodegeneration directly, by oxidation of lipids, proteins and DNA but also indirectly, by inducing a dysregulation of the immunity and favoring the state of pro-inflammatory response. In this review, we discuss the interrelated mechanisms of the impaired redox signaling, of which the most important are inflammation-induced production of free radicals by activated immune cells and growth factors, release of iron from myelin sheath during demyelination and mitochondrial dysfunction and consequent energy failure and impaired oxidative phosphorylation. Review also provides an overview of the interplay between inflammation, immunity and OS in MS. Finally, this review also points out new potential targets in MS regarding attenuation of OS and inflammatory response in MS.

Omics Integration for Mitochondria Systems Biology.

Significance: Elucidation of the central importance of mitophagy in homeostasis of cells and organisms emphasizes that mitochondrial functions extend far beyond short-term needs for energy production. In mitochondria systems biology, the mitochondrial genome, proteome, and metabolome operate as a functional network in coordination of cell activities. Organization occurs through subnetworks that are interconnected by membrane potential, transport activities, allosteric and cooperative interactions, redox signaling mechanisms, rheostatic control by post-translational modifications, and metal ion homeostasis. These subnetworks enable use of varied energy precursors, defense against environmental stressors, and macromolecular rewiring to titrate energy production, biosynthesis, and detoxification according to cell-specific needs. Rewiring mechanisms, termed mitochondrial reprogramming, enhance fitness to respond to metabolic resources and challenges from the environment. Maladaptive responses can cause cell death. Maladaptive rewiring can cause disease. In cancer, adaptive rewiring can interfere with effective treatment. Recent Advances: Many recent advances have been facilitated by the development of new omics tools, which create opportunities to use data-driven analysis of omics data to address these complex adaptive and maladaptive mechanisms of mitochondrial reprogramming in human disease. Critical Issues: Application of omics integration to model systems reveals a critical role for metal ion homeostasis broadly impacting mitochondrial reprogramming. Importantly, data show that trans-omics associations are more robust and biologically relevant than single omics associations. Future Directions: Application of omics integration to mitophagy research creates new opportunities to link the complex, interactive functions of mitochondrial form and function in mitochondria systems biology.

Increased formation of reactive oxygen species during tumor growth: Ex vivo low-temperature EPR and in vivo bioluminescence analyses

Previous studies have shown that reactive oxygen species (ROS) such as superoxide or hydrogen peroxide generated at low levels can exert a tumor-promoting role via a redox-signaling mechanism. Reports also suggest that both tumorigenesis and tumor growth are associated with enhanced ROS formation. However, whether ROS levels or ROS-derived oxidative marker levels increase during tumor growth remains unknown. In this study, in vivo bioluminescence imaging with a boronate-based pro-luciferin probe was used to assess ROS formation. Additionally, probe-free cryogenic electron paramagnetic resonance was used to quantify a characteristic aconitase [3Fe4S]+ center that arises in the tumor tissue of mouse xenografts from the reaction of the native [4Fe4S]2+ cluster with superoxide. Results indicated that tumor growth is accompanied by increased ROS formation, and revealed differences in oxidant formation in the inner and outer sections of tumor tissue, respectively, demonstrating redox heterogeneity. Studies using luciferin and pro-luciferin probes enabled the assessment of tumor size, ROS formation, and bioenergetic status (e.g., ATP) in luciferase-transfected mice tumor xenografts. Probe-free ex vivo low-temperature electron paramagnetic resonance can also be translated to clinical studies.

Perioperative Oxidative Stress: The Unseen Enemy.

Reactive oxygen species (ROS) are essential for cellular signaling and physiological function. An imbalance between ROS production and antioxidant protection results in a state of oxidative stress (OS), which is associated with perturbations in reduction/oxidation (redox) regulation, cellular dysfunction, organ failure, and disease. The pathophysiology of OS is closely interlinked with inflammation, mitochondrial dysfunction, and, in the case of surgery, ischemia/reperfusion injury (IRI). Perioperative OS is a complex response that involves patient, surgical, and anesthetic factors. The magnitude of tissue injury inflicted by the surgery affects the degree of OS, and both duration and nature of the anesthetic procedure applied can modify this. Moreover, the interindividual susceptibility to the impact of OS is likely to be highly variable and potentially linked to underlying comorbidities. The pathological link between OS and postoperative complications remains unclear, in part due to the complexities of measuring ROS- and OS-mediated damage. Exogenous antioxidant use and exercise have been shown to modulate OS and may have potential as countermeasures to improve postoperative recovery. A better understanding of the underlying mechanisms of OS, redox signaling, and regulation can provide an opportunity for patient-specific phenotyping and development of targeted interventions to reduce the disruption that surgery can cause to our physiology. Anesthesiologists are in a unique position to deliver countermeasures to OS and improve physiological resilience. To shy away from a process so fundamental to the welfare of these patients would be foolhardy and negligent, thus calling for an improved understanding of this complex facet of human biology.