Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Guzy, Robert D.; Sharma, Bhumika; Bell, Eric L.; Chandel, Navdeep S.; Schumacker, Paul T.

doi:10.1128/mcb.01338-07

Cited by 380 publications

(336 citation statements)

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“…By depleting RISP, the formation of ubisemiquinone at the Qo site is prevented, thus mimicking the response to myxothiazol. Taken together, these results are also consistent with a broader body of work indicating that hypoxia increases mitochondrial ROS signaling (10,17,18,(27)(28)(29)(36)(37)(38)(39).…”

Section: Discussionsupporting

confidence: 89%

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Waypa

Marks

Guzy

et al. 2013

Am J Respir Crit Care Med

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132

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Rationale: The role of reactive oxygen species (ROS) signaling in the O 2 sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses. Objectives: We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA). Methods: A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC). Measurements and Main Results: In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in [Ca 21 ] i . In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca 21 ] i of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice. Conclusions: Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca 21 ] i that cause acute hypoxic pulmonary vasoconstriction.Keywords: oxygen sensing; Rieske iron-sulfur protein; reactive oxygen species; roGFP; hypoxic pulmonary vasoconstrictionIn the lung, alveolar hypoxia triggers acute constriction of small pulmonary arteries (PA), a response termed hypoxic pulmonary vasoconstriction (HPV). This response is recapitulated in cultured PA smooth muscle cells (PASMC), indicating that the oxygen-sensing mechanism underlying HPV is intrinsic to the PASMC (1-12). Our previous work has implicated increases in reactive oxygen species (ROS) signaling during hypoxia (9,10, 12). Previous studies using mitochondrial inhibitors and mitochondria-deficient (r 0 ) cells suggested that the electron transport chain (ETC) is required for hypoxia-induced ROS signaling in the pulmonary circulation (9, 11-18). We subsequently assessed ROS signaling in hypoxic PASMC using roGFP, a thiol-containing, redox-sensitive reporter (19-23) targeted to compartments within mitochondria or the cytosol (10). Unlike other methods (24-26), this targeted approach permitted the differentiation of hypoxia-induced ROS changes between mitochondrial subcompartments. During hypoxia, increased oxidation was detected in the mitochondrial intermembrane space (IMS) and the cytoso...

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Section: Discussionsupporting

confidence: 89%

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Waypa

Marks

Guzy

et al. 2013

Am J Respir Crit Care Med

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132

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“…In addition to inhibiting PHDs directly, succinate may also indirectly stabilize HIF-1a by inducing ROS. It has been demonstrated that pharmacologic inhibition of succinate dehydrogenase (SDH), the enzyme responsible for the conversion of succinate to fumarate, or RNA interference of subunit B of SDH, induces HIF-1a stabilization in a ROSdependent manner [23]. ROS can affect HIF-1a by oxidizing Fe 2+ , a critical PHD cofactor, to Fe 3+ .…”

Section: Succinate and Hif-1a In Inflammationmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

512

407

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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“…Some reports indicate that damaged or mutated complex II is able to produce O 2 ·-; however, it is considered that all O 2 ·-due to complex II activity occurs at complex I due to reverse electron flow (Zhang et al, 1998;Guzy et al, 2008;Murphy, 2009). Although complex IV does not produce O 2 ·-itself, changes in its phosphorylation/dephosphorylation state can favour O 2 · production at the other RC points (Kadenbach et al, 2009).…”

Section: Oxidative Stressmentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

136

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Cited by 380 publications

References 53 publications

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Succinate: a metabolic signal in inflammation

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

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