Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature

2003 ◽  
Vol 284 (5) ◽  
pp. L710-L719 ◽  
Author(s):  
Renate Paddenberg ◽  
Barat Ishaq ◽  
Anna Goldenberg ◽  
Petra Faulhammer ◽  
Frank Rose ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Essential Role ◽  
Electron Flow ◽  
Enzymatic Reaction ◽  
Fumarate Reductase ◽  
Pulmonary Vasculature ◽  
Ros Generation ◽  
Ros Production ◽  
Complex Ii ◽  
Vascular Walls

In the pulmonary vasculature, the mechanisms responsible for oxygen sensing and the initiation of hypoxia-induced vasoconstriction and vascular remodeling are still unclear. Nitric oxide (NO) and reactive oxygen species (ROS) are discussed as early mediators of the hypoxic response. Here, we describe a quantitative analysis of NO- and ROS-producing cells within the vascular walls of murine lung sections cultured at normoxia or hypoxia. Whereas the number of NO-producing cells was not changed by hypoxia, the number of ROS-generating cells was significantly increased. Addition of specific inhibitors revealed that mitochondria were the source of ROS. The participation of the individual mitochondrial complexes differed in normoxic and hypoxic ROS generation. Whereas normoxic ROS production required complexes I and III, hypoxic ROS generation additionally demanded complex II. Histochemically demonstrable succinate dehydrogenase activity of complex II in the arterial wall decreased during hypoxia. Inhibition of the reversed enzymatic reaction, i.e., fumarate reductase, by application of succinate, specifically abolished hypoxic, but not normoxic, ROS generation. Thus complex II plays an essential role in hypoxic ROS production. Presumably, its catalytic activity switches from succinate dehydrogenase to fumarate reductase at reduced oxygen tension, thereby modulating the directionality of the electron flow.

CBSX3-Trxo-2 regulates ROS generation of mitochondrial complex II (succinate dehydrogenase) in Arabidopsis

Plant Science ◽  
2020 ◽  
Vol 294 ◽  
pp. 110458 ◽  
Author(s):  
Jin Seok Shin ◽  
Won Mi So ◽  
Soo Youn Kim ◽  
Minsoo Noh ◽  
Sujin Hyoung ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Ros Generation ◽  
Mitochondrial Complex ◽  
Complex Ii

Exercise training decreases rat heart mitochondria free radical generation but does not prevent Ca2+-induced dysfunction

2007 ◽  
Vol 102 (5) ◽  
pp. 1793-1798 ◽  
Author(s):  
Joseph W. Starnes ◽  
Brian D. Barnes ◽  
Marissa E. Olsen
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Electron Flow ◽  
Respiratory Control ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Ros Generation ◽  
Ros Production ◽  
Ptp Opening

Exercise provides cardioprotection against ischemia-reperfusion injury, a process involving mitochondrial reactive oxygen species (ROS) generation and calcium overload. This study tested the hypotheses that isolated mitochondria from hearts of endurance-trained rats have decreased ROS production and improved tolerance against Ca2+-induced dysfunction. Male Fischer 344 rats were either sedentary (Sed, n = 8) or endurance exercise trained (ET, n = 11) by running on a treadmill for 16 wk (5 days/wk, 60 min/day, 25 m/min, 6° grade). Mitochondrial oxidative phosphorylation measures were determined with glutamate-malate or succinate as substrates, and H2O2 production and permeability transition pore (PTP) opening were determined with succinate. All assays were carried out in the absence and presence of calcium. In response to 25 and 50 μM CaCl2, Sed and ET displayed similar decreases in state 3 respiration, respiratory control ratio, and ADP:O ratio. Ca2+-induced PTP opening was also similar. However, H2O2 production by ET was lower than Sed ( P < 0.05) in the absence of calcium (323 ± 12 vs. 362 ± 11 pmol·min−1·mg protein−1) and the presence of 50 μM CaCl2 (154 ± 3 vs. 197 ± 7 pmol·min−1·mg protein−1). Rotenone, which blocks electron flow from succinate to complex 1, reduced H2O2 production and eliminated differences between ET and Sed. Mitochondrial superoxide dismutase and glutathione peroxidase were not affected by exercise. Catalase activity was extremely low but increased 49% in ET ( P < 0.05). In conclusion, exercise reduces ROS production in myocardial mitochondria through adaptations specific to complex 1 but does not improve mitochondrial tolerance to calcium overload.

Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection

2003 ◽  
Vol 284 (4) ◽  
pp. H1048-H1056 ◽  
Author(s):  
Petras P. Dzeja ◽  
Peter Bast ◽  
Cevher Ozcan ◽  
Arturo Valverde ◽  
Ekshon L. Holmuhamedov ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Respiratory Chain ◽  
Ischemia Reperfusion ◽  
Electron Flow ◽  
Mitochondrial Respiratory Chain ◽  
Ros Generation ◽  
Mitochondrial Atpase ◽  
Cellular Protection ◽  
Myocardial Energetics ◽  
Nucleotide Degradation

Modulation of mitochondrial respiratory chain, dehydrogenase, and nucleotide-metabolizing enzyme activities is fundamental to cellular protection. Here, we demonstrate that the potassium channel opener diazoxide, within its cardioprotective concentration range, modulated the activity of flavin adenine dinucleotide-dependent succinate dehydrogenase with an IC50 of 32 μM and reduced the rate of succinate-supported generation of reactive oxygen species (ROS) in heart mitochondria. 5-Hydroxydecanoic fatty acid circumvented diazoxide-inhibited succinate dehydrogenase-driven electron flow, indicating a metabolism-dependent supply of redox equivalents to the respiratory chain. In perfused rat hearts, diazoxide diminished the generation of malondialdehyde, a marker of oxidative stress, which, however, increased on diazoxide washout. This effect of diazoxide mimicked ischemic preconditioning and was associated with reduced oxidative damage on ischemia-reperfusion. Diazoxide reduced cellular and mitochondrial ATPase activities, along with nucleotide degradation, contributing to preservation of myocardial ATP levels during ischemia. Thus, by targeting nucleotide-requiring enzymes, particularly mitochondrial succinate dehydrogenase and cellular ATPases, diazoxide reduces ROS generation and nucleotide degradation, resulting in preservation of myocardial energetics under stress.

scholarly journals Increased Succinate Accumulation Induces ROS Generation in In Vivo Ischemia/Reperfusion-Affected Rat Kidney Mitochondria

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Justina Kamarauskaite ◽  
Rasa Baniene ◽  
Darius Trumbeckas ◽  
Arvydas Strazdauskas ◽  
Sonata Trumbeckaite
Keyword(s):  
Succinate Dehydrogenase ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Complex Ii ◽  
Kidney Mitochondria ◽  
New Findings ◽  
Kidney Ischemia

Mitochondria are recognized as main reactive oxygen species (ROS) producers, involving ROS generation by mitochondrial complexes I and III. Lately, the focus has been shifting to the ROS generation by complex II. Contribution of complex II (SDH) to ROS generation still remains debatable, especially in in vivo settings. Moreover, it is not completely defined at what time of ischemia the first alterations in mitochondria and the cell begin, which is especially important with renal arterial clamping in vivo during kidney surgery, as it predicts the postischemic kidney function. The aim of this study on an in vivo rat kidney ischemia/reperfusion model was to determine if there is a connection among (a) duration of kidney ischemia and mitochondrial dysfunction and (b) succinate dehydrogenase activity, succinate accumulation, and ROS generation in mitochondria at low and saturating succinate concentrations. Our results point out that (1) mitochondrial disturbances can occur even after 30 min of kidney ischemia/reperfusion in vivo and increase progressively with the prolonged time of ischemia; (2) accumulation of succinate in cytosol after ischemia/reperfusion correlated with increased H2O2 generation mediated by complex II, which was most noticeable with physiological succinate concentrations; and (3) ischemia/reperfusion induced cell necrosis, indicated by the changes in LDH activity. In conclusion, our new findings on the accumulation of succinate in cytosol and changes in SDH activity during kidney ischemia/reperfusion may be important for energy production after reperfusion, when complex I activity is suppressed. On the other hand, an increased activity of succinate dehydrogenase is associated with the increased ROS generation, especially with physiological succinate concentrations. All these observations play an important role in understanding the mechanisms which occur in the early phase of ischemia/reperfusion injury in vivo and may provide new ideas for novel therapeutic approaches or injury prevention; therefore, more detailed studies are necessary in the future.

scholarly journals Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation–reduction state

2002 ◽  
Vol 368 (2) ◽  
pp. 545-553 ◽  
Author(s):  
Yulia KUSHNAREVA ◽  
Anne N. MURPHY ◽  
Alexander ANDREYEV
Keyword(s):  
Reactive Oxygen Species ◽  
Cytochrome C ◽  
Complex I ◽  
Electron Flow ◽  
Reactive Oxygen ◽  
Complex Iii ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Reduced State

Several lines of evidence indicate that mitochondrial reactive oxygen species (ROS) generation is the major source of oxidative stress in the cell. It has been shown that ROS production accompanies cytochrome c release in different apoptotic paradigms, but the site(s) of ROS production remain obscure. In the current study, we demonstrate that loss of cytochrome c by mitochondria oxidizing NAD+-linked substrates results in a dramatic increase of ROS production and respiratory inhibition. This increased ROS production can be mimicked by rotenone, a complex I inhibitor, as well as other chemical inhibitors of electron flow that act further downstream in the electron transport chain. The effects of cytochrome c depletion from mitoplasts on ROS production and respiration are reversible upon addition of exogenous cytochrome c. Thus in these models of mitochondrial injury, a primary site of ROS generation in both brain and heart mitochondria is proximal to the rotenone inhibitory site, rather than in complex III. ROS production at complex I is critically dependent upon a highly reduced state of the mitochondrial NAD(P)+ pool and is achieved upon nearly complete inhibition of the respiratory chain. Redox clamp experiments using the acetoacetate/d-β-hydroxybutyrate couple in the presence of a maximally inhibitory rotenone concentration suggest that the site is approx. 50mV more electronegative than the NADH/NAD+ couple. In the absence of inhibitors, this highly reduced state of mitochondria can be induced by reverse electron flow from succinate to NAD+, accounting for profound ROS production in the presence of succinate. These results lead us to propose a model of thermodynamic control of mitochondrial ROS production which suggests that the ROS-generating site of complex I is the Fe—S centre N-1a.

Mitochondrial Ca2+-induced K+ influx increases respiration and enhances ROS production while maintaining membrane potential

2007 ◽  
Vol 292 (1) ◽  
pp. C148-C156 ◽  
Author(s):  
André Heinen ◽  
Amadou K. S. Camara ◽  
Mohammed Aldakkak ◽  
Samhita S. Rhodes ◽  
Matthias L. Riess ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Respiration ◽  
Channel Blocker ◽  
Electron Flow ◽  
Ros Generation ◽  
Ros Production ◽  
Guinea Pig Heart ◽  
Isolated Hearts ◽  
Channel Opening ◽  
Charged Membrane

We recently demonstrated a role for altered mitochondrial bioenergetics and reactive oxygen species (ROS) production in mitochondrial Ca2+-sensitive K+ (mtKCa) channel opening-induced preconditioning in isolated hearts. However, the underlying mitochondrial mechanism by which mtKCa channel opening causes ROS production to trigger preconditioning is unknown. We hypothesized that submaximal mitochondrial K+ influx causes ROS production as a result of enhanced electron flow at a fully charged membrane potential (ΔΨm). To test this hypothesis, we measured effects of NS-1619, a putative mtKCa channel opener, and valinomycin, a K+ ionophore, on mitochondrial respiration, ΔΨm, and ROS generation in guinea pig heart mitochondria. NS-1619 (30 μM) increased state 2 and 4 respiration by 5.2 ± 0.9 and 7.3 ± 0.9 nmol O2·min−1·mg protein−1, respectively, with the NADH-linked substrate pyruvate and by 7.5 ± 1.4 and 11.6 ± 2.9 nmol O2·min−1·mg protein−1, respectively, with the FADH2-linked substrate succinate (+ rotenone); these effects were abolished by the mtKCa channel blocker paxilline. ΔΨm was not decreased by 10–30 μM NS-1619 with either substrate, but H2O2 release was increased by 44.8% (65.9 ± 2.7% by 30 μM NS-1619 vs. 21.1 ± 3.8% for time controls) with succinate + rotenone. In contrast, NS-1619 did not increase H2O2 release with pyruvate. Similar results were found for lower concentrations of valinomycin. The increase in ROS production in succinate + rotenone-supported mitochondria resulted from a fully maintained ΔΨm, despite increased respiration, a condition that is capable of allowing increased electron leak. We propose that mild matrix K+ influx during states 2 and 4 increases mitochondrial respiration while maintaining ΔΨm; this allows singlet electron uptake by O2 and ROS generation.

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