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Mitochondria are quantifiably the most important sources of superoxide (O2●−) and hydrogen peroxide (H2O2) in mammalian cells. The overproduction of these molecules has been studied mostly in the contexts of the pathogenesis of human diseases and aging. However, controlled bursts in mitochondrial ROS production, most notably H2O2, also plays a vital role in the transmission of cellular information. Striking a balance between utilizing H2O2 in second messaging whilst avoiding its deleterious effects requires the use of sophisticated feedback control and H2O2 degrading mechanisms. Mitochondria are enriched with H2O2 degrading enzymes to desensitize redox signals. These organelles also use a series of negative feedback loops, such as proton leaks or protein S-glutathionylation, to inhibit H2O2 production. Understanding how mitochondria produce ROS is also important for comprehending how these organelles use H2O2 in eustress signaling. Indeed, twelve different enzymes associated with nutrient metabolism and oxidative phosphorylation (OXPHOS) can serve as important ROS sources. This includes several flavoproteins and respiratory complexes I-III. Progress in understanding how mitochondria generate H2O2 for signaling must also account for critical physiological factors that strongly influence ROS production, such as sex differences and genetic variances in genes encoding antioxidants and proteins involved in mitochondrial bioenergetics. In the present review, I provide an updated view on how mitochondria budget cellular H2O2 production. These discussions will focus on the potential addition of two acyl-CoA dehydrogenases to the list of ROS generators and the impact of important phenotypic and physiological factors such as tissue type, mouse strain, and sex on production by these individual sites.

For over 40 years, mitochondrial reactive oxygen species (ROS) production and balance has been studied in the context of oxidative distress and tissue damage. However, research over the past decade has demonstrated that the mitochondria have a more complicated relationship with ROS. Superoxide (O2•−) and hydrogen peroxide (H2O2) are the proximal ROS formed by the mitochondria, and the latter molecule is used as a secondary messenger to coordinate oxidative metabolism with changes in cell physiology. Like any other secondary messenger, H2O2 levels need to be regulated through its production and degradation and the mitochondria are enriched with the antioxidant defenses required to degrade ROS formed by nutrient oxidation and respiration. Recent work has also demonstrated that these antioxidant systems also carry the capacity to clear H2O2 formed outside of mitochondria. These observations led to the development of the postulate that the mitochondria serve as “ROS stabilizing devices” that buffer cellular H2O2 levels. Here, I provide an updated view on mitochondrial ROS homeostasis and discuss the “ROS stabilizing” function of the mitochondria in mammalian cells. This will be followed by a hypothetical discussion on the potential function of the mitochondria and proton motive force in degrading cellular H2O2 signals emanating from cytosolic enzymes.

Oxidation–reduction (redox) reactions are central to the existence of life. Reactive species of oxygen, nitrogen and sulfur mediate redox control of a wide range of essential cellular processes. Yet, excessive levels of oxidants are associated with ageing and many diseases, including cardiological and neurodegenerative diseases, and cancer. Hence, maintaining the fine-tuned steady-state balance of reactive species production and removal is essential. Here, we discuss new insights into the dynamic maintenance of redox homeostasis (that is, redox homeodynamics) and the principles underlying biological redox organization, termed the ‘redox code’. We survey how redox changes result in stress responses by hormesis mechanisms, and how the lifelong cumulative exposure to environmental agents, termed the ‘exposome’, is communicated to cells through redox signals. Better understanding of the molecular and cellular basis of redox biology will guide novel redox medicine approaches aimed at preventing and treating diseases associated with disturbed redox regulation.Oxidation–reduction (redox) reactions involving reactive oxygen, nitrogen and sulfur species are vital for life, but excessive oxidant levels contribute to ageing and diseases. This Review explores cellular dynamics of redox homeostasis, such as responses to oxidative and reductive stresses and intracellular and intercellular redox communication pathways.

Human primary myotubes are highly glycolytic when cultured in high glucose medium rendering it difficult to study mitochondrial dysfunction. Galactose is known to enhance mitochondrial metabolism and could be an excellent model to study mitochondrial dysfunction in human primary myotubes. The aim of the present study was to 1) characterize the effect of differentiating healthy human myoblasts in galactose on oxidative metabolism and 2) determine whether galactose can pinpoint a mitochondrial malfunction in post-diabetic myotubes. Oxygen consumption rate (OCR), lactate levels, mitochondrial content, citrate synthase and cytochrome C oxidase activities, and AMPK phosphorylation were determined in healthy myotubes differentiated in different sources/concentrations of carbohydrates: 25 mM glucose (high glucose (HG)), 5 mM glucose (low glucose (LG)) or 10 mM galactose (GAL). Effect of carbohydrates on OCR was also determined in myotubes derived from post-diabetic patients and matched obese non-diabetic subjects. OCR was significantly increased whereas anaerobic glycolysis was significantly decreased in GAL myotubes compared to LG or HG myotubes. This increased OCR in GAL myotubes occurred in conjunction with increased cytochrome C oxidase activity and expression, as well as increased AMPK phosphorylation. OCR of post-diabetic myotubes was not different than that of obese non-diabetic myotubes when differentiated in LG or HG. However, whereas GAL increased OCR in obese non-diabetic myotubes, it did not affect OCR in post-diabetic myotubes, leading to a significant difference in OCR between groups. The lack of an increase in OCR in post-diabetic myotubes differentiated in GAL was in relation with unaltered cytochrome C oxidase activity levels or AMPK phosphorylation. Our results indicate that differentiating human primary myoblasts in GAL enhances aerobic metabolism. Because this cell culture model elicited an abnormal response in cells from post-diabetic patients, it may be useful in further studies of the molecular mechanisms of mitochondrial dysfunction.

Mitochondrial uncoupling proteins (UCP) 1-3 fulfill many physiological functions, ranging from non-shivering thermogenesis (UCP1) to glucose-stimulated insulin release (GSIS) and satiety signaling (UCP2) and muscle fuel metabolism (UCP3). Several studies have suggested that UCPs mediate these functions by facilitating proton return to the matrix. This would decrease protonic backpressure on the respiratory chain, lowering the production of hydrogen peroxide (H2O2), a second messenger. However, controlling mitochondrial H2O2 production to prevent oxidative stress by activating these leaks through these proteins is still enthusiastically debated. This is due to compelling evidence that UCP2/3 fulfill other function(s) and the inability to reproduce findings that UCP1-3 use inducible leaks to control reactive oxygen species (ROS) production. Further, other studies have found that UCP2/3 may serve as Ca2+. Therefore, we performed a systematic review aiming to summarize the results collected on the topic. A literature search using a list of curated keywords in Pubmed, BIOSIS Citation Index and Scopus was conducted. Potentially relevant references were screened, duplicate references eliminated, and then literature titles and abstracts were evaluated using Rayyan software. A total of 1101 eligible studies were identified for the review. From this total, 416 studies were evaluated based on our inclusion criteria. In general, most studies identified a role for UCPs in preventing oxidative stress, and in some cases, this may be related to the induction of leaks and lowering protonic backpressure on the respiratory chain. However, some studies also generated evidence that UCP2/3 may mitigate oxidative stress by transporting Ca2+ into the matrix, exporting lipid hydroperoxides, or by transporting C-4 metabolites. Additionally, some showed that activating UCP1 or 3 can increase mitochondrial ROS production, even though there is still augmented protection from oxidative stress. Conclusion: Overall, most available studies demonstrate that UCPs, particularly UCP2/3, prevent oxidative stress. However, the mechanism utilized to do so remains elusive and raises the question that UCP2/3 should be renamed, since they may still not be true “uncoupling proteins”.

α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty acid catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc is its ability to sense changes in the redox environment through the reversible oxidation of the vicinal lipoic acid thiols of its dihydrolipoamide succinyltransferase (DLST; E2) subunit, which controls its activity and, by extension, OxPhos. This characteristic inculcates KGDHc with redox regulatory properties for the modulation of metabolism and mediating of intra- and intercellular signals. The innate capacity of KGDHc to participate in the regulation of cell redox homeodynamics also occurs through the production of mitochondrial hydrogen peroxide (mtH2O2), which is generated by the dihydrolipoamide dehydrogenase (DLD; E3) downstream from the E2 subunit. Reversible covalent redox modification of the E2 subunit controls this mtH2O2 production by KGDHc, which not only protects from oxidative distress but also modulates oxidative eustress pathways. The importance of KGDHc in modulating redox homeodynamics is underscored by the pathogenesis of neurological and metabolic disorders that occur due to the hyper-generation of mtH2O2 by this enzyme complex. This also implies that the targeted redox modification of the E2 subunit could be a potential therapeutic strategy for limiting the oxidative distress triggered by KGDHc mtH2O2 hyper-generation. In this short article, I will discuss recent findings demonstrating KGDHc is a potent mtH2O2 source that can trigger the manifestation of several neurological and metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), inflammation, and cancer, and the targeted redox modification of the E2 subunit could alleviate these syndromes.

Urban parks became critical for maintaining the well-being of urban residents during the COVID-19 global pandemic. To examine the impact of COVID-19 on urban park usage, we selected New York City (NYC) and used SafeGraph mobility data, which was collected from a large sample of mobile phone users, to assess the change in park visits and travel distance to a park based on 1) park type, 2) the income level of the visitor census block group (visitor CBG) and 3) that of the park census block group (park CBG). All analyses were adjusted for the impact of temperature on park visitation, and we focused primarily on visits made by NYC residents. Overall, for the eight most popular park types in NYC, visits dropped by 49.2% from 2019 to 2020. The peak reduction in visits occurred in April 2020. Visits to all park types, excluding Nature Areas, decreased from March to December 2020 as compared to 2019. Parks located in higher-income CBGs tended to have lower reductions in visits, with this pattern being primarily driven by large parks, including Flagship Parks, Community Parks and Nature Areas. All types of parks saw significant decreases in distance traveled to visit them, with the exception of the Jointly Operated Playground, Playground, and Nature Area park types. Visitors originating from lower-income CBGs traveled shorter distances to parks and had less reduction in travel distances compared to those from higher-income CBGs. Furthermore, both before and during the pandemic, people tended to travel a greater distance to parks located in high-income CBGs compared to those in low-income CBGs. Finally, multiple types of parks proved crucial destinations for NYC residents during the pandemic. This included Nature Areas to which the visits remained stable, along with Recreation Field/Courts which had relatively small decreases in visits, especially for lower-income communities. Results from this study can support future park planning by shedding light on the different uses of certain park types before and during a global crisis, when access to these facilities can help alleviate the human well-being consequences of “lockdown” policies.

Although circadian biorhythms of mitochondria and cells are highly conserved and crucial for the well-being of complex animals, there is a paucity of studies on the reciprocal interactions between oxidative stress, redox modifications, metabolism, thermoregulation, and other major oscillatory physiological processes. To address this limitation, we hypothesize that circadian/ultradian interaction of the redoxome, bioenergetics, and temperature signaling strongly determine the differential activities of the sleep–wake cycling of mammalians and birds. Posttranslational modifications of proteins by reversible cysteine oxoforms, S-glutathionylation and S-nitrosylation are shown to play a major role in regulating mitochondrial reactive oxygen species production, protein activity, respiration, and metabolomics. Nuclear DNA repair and cellular protein synthesis are maximized during the wake phase, whereas the redoxome is restored and mitochondrial remodeling is maximized during sleep. Hence, our analysis reveals that wakefulness is more protective and restorative to the nucleus (nucleorestorative), whereas sleep is more protective and restorative to mitochondria (mitorestorative). The “redox–bioenergetics–temperature and differential mitochondrial–nuclear regulatory hypothesis” adds to the understanding of mitochondrial respiratory uncoupling, substrate cycling control and hibernation. Similarly, this hypothesis explains how the oscillatory redox–bioenergetics–temperature–regulated sleep–wake states, when perturbed by mitochondrial interactome disturbances, influence the pathogenesis of aging, cancer, spaceflight health effects, sudden infant death syndrome, and diseases of the metabolism and nervous system.

Confining clay layers typically protect groundwater aquifers against downward intrusion of contaminants. In the context of groundwater arsenic in Bangladesh, we challenge this notion here by showing that organic carbon drawn from a clay layer into a low-arsenic pre-Holocene (>12 kyr-old) aquifer promotes the reductive dissolution of iron oxides and the release of arsenic. The finding explains a steady rise in arsenic concentrations in a pre-Holocene aquifer below such a clay layer and the repeated failure of a structurally sound community well. Tritium measurements indicate that groundwater from the affected depth interval (40–50 m) was recharged >60 years ago. Deeper (55–65 m) groundwater in the same pre-Holocene aquifer was recharged only 10–50 years ago but is still low in arsenic. Proximity to a confining clay layer that expels organic carbon as an indirect response to groundwater pumping, rather than directly accelerated recharge, caused arsenic contamination of this pre-Holocene aquifer. Generally it is thought that confining clay layers provide protection to low-arsenic groundwaters against intrusion of shallower, high-arsenic groundwater bodies. Here, the authors show that impermeable clay layers can increase arsenic input to underlying groundwater systems due to reduction of iron oxides coupled to carbon oxidation.

Background: It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent modification has been identified as a cell-wide signaling platform required for embryonic development and regulation of many physiological functions. Scope of the Review: Mitochondria use hydrogen peroxide (H2O2) as a second messenger, but its availability must be controlled to prevent oxidative distress and promote changes in cell behavior in response to stimuli. Experimental data favor the function of protein S-glutathionylation as a feedback loop for the inhibition of mitochondrial H2O2 production. Major conclusions: The glutathione pool redox state is linked to the availability of H2O2, making glutathionylation an ideal mechanism for preventing oxidative distress whilst playing a part in desensitizing mitochondrial redox signals. General Significance: The biological significance of glutathionylation is rooted in redox status communication. The present review critically evaluates the experimental evidence supporting its role in negating mitochondrial H2O2 production for cell signaling and prevention of electrophilic stress.