The thioredoxin and glutathione-dependent H2O2 consumption pathways in muscle mitochondria: Involvement in H2O2 metabolism and consequence to H2O2 efflux assays

Munro, Daniel; Banh, Sheena; Sotiri, Emianka; Tamanna, Nahid; Treberg, Jason R.

doi:10.1016/j.freeradbiomed.2016.04.014

Cited by 61 publications

(64 citation statements)

References 59 publications

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“…This is, in fact, the case for H 2 O 2 production for many respiratory substrates in rodent skeletal muscle ( Fig. 1D; Treberg et al, 2015;Munro et al, 2016) and brain mitochondria (Starkov et al, 2014). An additional condition promoting metabolic regulation is that consumption of the metabolite should be able to respond to changes in production.…”

Section: Regulation Of Metabolite Concentrationmentioning

confidence: 62%

“…It is conventionally assumed that only minor amounts of H 2 O 2 produced in the mitochondrial matrix are consumed before reaching the extramitochondrial detection system. However, using rodent skeletal muscle mitochondria, we recently demonstrated that this is not the case (Treberg et al, 2010(Treberg et al, , 2015Munro et al, 2016). This means that mitochondrial ROS production rates are largely underestimated when based on extramitochondrial detection of H 2 O 2 .…”

Section: This Is Illustrated Inmentioning

confidence: 98%

“…However, the assumption of a simple first-order reaction describing the combined consumers of ROS allows for consumption to be infinitely high at infinite H 2 O 2 concentration. An infinite value of V c is, of course, unrealistic; the ROS consumers do appear to approach saturation (Banh and Treberg, 2013;Munro et al, 2016 ; this is because components of the assay system that is used to quantify H 2 O 2 cannot cross biological membranes and are confined to the medium. It is conventionally assumed that only minor amounts of H 2 O 2 produced in the mitochondrial matrix are consumed before reaching the extramitochondrial detection system.…”

Section: This Is Illustrated Inmentioning

confidence: 99%

“…2D). If the matrix H 2 O 2 consumption capacity is inhibited with auranofin, which impairs the thioredoxin-dependent pathway (Munro et al, 2016), the slope of the relationship between V p,app and V c,app decreases, and the predicted rate of H 2 O 2 consumption, in the absence of competition from endogenous production, also decreases.…”

Section: This Is Illustrated Inmentioning

confidence: 99%

“…and J.R.T. ; n=4; based on protocols described in Munro et al, 2016) for V p,app and V c,app . All values are means± s.e.m.…”

Section: Implications and Future Workmentioning

confidence: 99%

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A radical shift in perspective: mitochondria as regulators of reactive oxygen species

Munro

Treberg

2017

Journal of Experimental Biology

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177

123

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Mitochondria are widely recognized as a source of reactive oxygen species (ROS) in animal cells, where it is assumed that overproduction of ROS leads to an overwhelmed antioxidant system and oxidative stress. In this Commentary, we describe a more nuanced model of mitochondrial ROS metabolism, where integration of ROS production with consumption by the mitochondrial antioxidant pathways may lead to the regulation of ROS levels. Superoxide and hydrogen peroxide (H 2 O 2 ) are the main ROS formed by mitochondria. However, superoxide, a free radical, is converted to the non-radical, membrane-permeant H 2 O 2 ; consequently, ROS may readily cross cellular compartments. By combining measurements of production and consumption of H 2 O 2 , it can be shown that isolated mitochondria can intrinsically approach a steady-state concentration of H 2 O 2 in the medium. The central hypothesis here is that mitochondria regulate the concentration of H 2 O 2 to a value set by the balance between production and consumption. In this context, the consumers of ROS are not simply a passive safeguard against oxidative stress; instead, they control the established steady-state concentration of H 2 O 2 . By considering the response of rat skeletal muscle mitochondria to high levels of ADP, we demonstrate that H 2 O 2 production by mitochondria is far more sensitive to changes in mitochondrial energetics than is H 2 O 2 consumption; this concept is further extended to evaluate how the muscle mitochondrial H 2 O 2 balance should respond to changes in aerobic work load. We conclude by considering how differences in the ROS consumption pathways may lead to important distinctions amongst tissues, along with briefly examining implications for differing levels of activity, temperature change and metabolic depression.

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Section: Regulation Of Metabolite Concentrationmentioning

confidence: 62%

Section: This Is Illustrated Inmentioning

confidence: 98%

Section: This Is Illustrated Inmentioning

confidence: 99%

Section: This Is Illustrated Inmentioning

confidence: 99%

“…and J.R.T. ; n=4; based on protocols described in Munro et al, 2016) for V p,app and V c,app . All values are means± s.e.m.…”

Section: Implications and Future Workmentioning

confidence: 99%

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A radical shift in perspective: mitochondria as regulators of reactive oxygen species

Munro

Treberg

2017

Journal of Experimental Biology

Self Cite

177

123

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The influence of redox modulation on hypoxic endothelial cell metabolic and proteomic profiles through a small thiol‐based compound tuning glutathione and thioredoxin systems

et al. 2023

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Reduction in oxygen levels is a key feature in the physiology of the bone marrow (BM) niche where hematopoiesis occurs. The BM niche is a highly vascularized tissue and endothelial cells (ECs) support and regulate blood cell formation from hematopoietic stem cells (HSCs). While in vivo studies are limited, ECs when cultured in vitro at low O2 (<5%), fail to support functional HSC maintenance due to oxidative environment. Therefore, changes in EC redox status induced by antioxidant molecules may lead to alterations in the cellular response to hypoxia likely favoring HSC self‐renewal. To evaluate the impact of redox regulation, HUVEC, exposed for 1, 6, and 24 h to 3% O2 were treated with N‐(N‐acetyl‐l‐cysteinyl)‐S‐acetylcysteamine (I‐152). Metabolomic analyses revealed that I‐152 increased glutathione levels and influenced the metabolic profiles interconnected with the glutathione system and the redox couples NAD(P)+/NAD(P)H. mRNA analysis showed a lowered gene expression of HIF‐1α and VEGF following I‐152 treatment whereas TRX1 and 2 were stimulated. Accordingly, the proteomic study revealed the redox‐dependent upregulation of thioredoxin and peroxiredoxins that, together with the glutathione system, are the main regulators of intracellular ROS. Indeed, a time‐dependent ROS production under hypoxia and a quenching effect of the molecule were evidenced. At the secretome level, the molecule downregulated IL‐6, MCP‐1, and PDGF‐bb. These results suggest that redox modulation by I‐152 reduces oxidative stress and ROS level in hypoxic ECs and may be a strategy to fine‐tune the environment of an in vitro BM niche able to support functional HSC maintenance.

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Renal Epithelial Mitochondria: Implications for Hypertensive Kidney Disease

Stadler,

Ilatovskaya

2023

Comprehensive Physiology

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According to the Centers for Disease Control and Prevention, 1 in 2 U.S. adults have hypertension, and more than 1 in 7 chronic kidney disease. In fact, hypertension is the second leading cause of kidney failure in the United States; it is a complex disease characterized by, leading to, and caused by renal dysfunction. It is well‐established that hypertensive renal damage is accompanied by mitochondrial damage and oxidative stress, which are differentially regulated and manifested along the nephron due to the diverse structure and functions of renal cells. This article provides a summary of the relevant knowledge of mitochondrial bioenergetics and metabolism, focuses on renal mitochondrial function, and discusses the evidence that has been accumulated regarding the role of epithelial mitochondrial bioenergetics in the development of renal tissue dysfunction in hypertension. © 2024 American Physiological Society. Compr Physiol 14:5225‐5242, 2024.

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The thioredoxin and glutathione-dependent H2O2 consumption pathways in muscle mitochondria: Involvement in H2O2 metabolism and consequence to H2O2 efflux assays

Cited by 61 publications

References 59 publications

A radical shift in perspective: mitochondria as regulators of reactive oxygen species

A radical shift in perspective: mitochondria as regulators of reactive oxygen species

The influence of redox modulation on hypoxic endothelial cell metabolic and proteomic profiles through a small thiol‐based compound tuning glutathione and thioredoxin systems

Renal Epithelial Mitochondria: Implications for Hypertensive Kidney Disease

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