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Review
. 2017 Jun;174(12):1670-1689.
doi: 10.1111/bph.13403. Epub 2016 Feb 4.

Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function

Andreas Daiber  1 , Fabio Di Lisa  2 , Matthias Oelze  1 , Swenja Kröller-Schön  1 , Sebastian Steven  1   3 , Eberhard Schulz  1 , Thomas Münzel  1
Affiliations
Review

Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function

Andreas Daiber et al. Br J Pharmacol. 2017 Jun.

Abstract

Cardiovascular diseases are associated with and/or caused by oxidative stress. This concept has been proven by using the approach of genetic deletion of reactive species producing (pro-oxidant) enzymes as well as by the overexpression of reactive species detoxifying (antioxidant) enzymes leading to a marked reduction of reactive oxygen and nitrogen species (RONS) and in parallel to an amelioration of the severity of diseases. Likewise, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of antioxidant RONS detoxifying enzymes. Thus, the consequences of the interaction (redox crosstalk) of superoxide/hydrogen peroxide produced by mitochondria with other ROS producing enzymes such as NADPH oxidases (Nox) are of outstanding importance and will be discussed including the consequences for endothelial nitric oxide synthase (eNOS) uncoupling as well as the redox regulation of the vascular function/tone in general (soluble guanylyl cyclase, endothelin-1, prostanoid synthesis). Pathways and potential mechanisms leading to this crosstalk will be analysed in detail and highlighted by selected examples from the current literature including hypoxia, angiotensin II-induced hypertension, nitrate tolerance, aging and others. The general concept of redox-based activation of RONS sources via "kindling radicals" and enzyme-specific "redox switches" will be discussed providing evidence that mitochondria represent key players and amplifiers of the burden of oxidative stress.

Linked articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

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Figures

Figure 1
Figure 1
Indirect proof for the prognostic importance of oxidative stress. In patients with high oxidative stress in forearm vessels, compatible with a vitamin C response on endothelial function above the median, had within the next 5 years more cardiovascular events such as myocardial infarction, stroke, coronary and peripheral revascularization procedures as compared to patients with a vitamin C response below the median. Endothelial function was assessed by venous plethysmography and intraarterial infusion of the endothelium‐dependent vasodilator acetylcholine. Modified from Heitzer et al. and Münzel, Circulation 2001 (Heitzer et al., 2001a). With permission of Wolters Kluwer Health. Copyright 2001.
Figure 2
Figure 2
Redox regulation of the vascular tone. Potential „redox switches“in endothelial NO synthase (eNOS) are based on S‐glutathionylation of cysteines in the reductase domain, H2O2/ONOO− mediated activation of PKC and protein tyrosine kinase‐2 (PYK‐2) dependent eNOS phosphorylation, direct oxidative depletion of the eNOS cofactor BH4, oxidative disruption of the zinc‐sulphur‐complex in the dimer binding interface and regulation of ADMA synthesis/break‐down by oxidants. Potential „redox switches“in soluble guanylyl cyclase (sGC) are based on S‐nitrosation by species such as N2O3 or S‐oxidation of regulatory cysteines as well as oxidation (depletion) of the heme moiety. An additional “redox switch” comprises the endothelin‐1 (ET‐1) and NADPH oxidase (Nox) system since oxidants can lead to increased expression of ET‐1 and potentiate its vasoconstrictory properties, which can be further self‐amplified by ET‐1 dependent activation of NADPH oxidase. Finally, prostanoid synthesis (Cox and PGIS) represents a “redox switch” since the key enzyme of prostanoid synthesis, cyclooxygenase, is activated at low peroxide levels and nitrated/inactivated at high peroxynitrite or nitrite/H2O2 concentrations, whereas PGIS is nitrated/inactivated by peroxynitrite and both oxidative alterations may significantly shift the prostanoid profile from vasodilatory to vasoconstrictory conditions. Activation of all of these redox switches by ROS and RNS (most likely hydrogen peroxide, peroxynitrite or superoxide) alters endothelial and vascular function, which will favour vasoconstriction and/or the development of arterial hypertension. Any of these switches can be activated in a certain disease condition but usually they are simultaneously activated and one finds eNOS uncoupling, sGC desensitization and PGIS nitration along with increased COX activity or up‐regulated ET‐1 signalling at the same time.
Figure 3
Figure 3
(A) Who's the bad guy – or which biological source of ROS formation is the most detrimental one? Likely candidates are mitochondrial ROS formation (mitochondrial superoxide/hydrogen peroxide), NADPH oxidases (Nox1, Nox2, Nox4), uncoupled eNOS (uc‐eNOS) or xanthine oxidase (XO). The most challenging task for the future is the discrimination between beneficial and detrimental effects of ROS formation and signalling. (A) Direct correlation between vascular ROS formation and endothelial function. Endothelial function (measured by isometric tension recording, efficacy in %) inversely correlates with NADPH oxidase activity (measured by lucigenin‐derived chemiluminescence [superoxide formation] in membrane fractions; expressed as RLU/min) in experimental type 1 diabetes mellitus and therapy with organic nitrates pentaerithrityl tetranitrate (PETN, beneficial effects) vs. isosorbide‐5‐mononitrate (ISMN, adverse effects). Type 1 diabetes mellitus is associated with activation of all ROS sources and organic nitrates such as isosorbide‐5‐mononitrate further aggravate these complications. Retraced from original data of Schuhmacher et al. and Daiber, Diabetes 2011 (Schuhmacher et al., 2011). (B) Endothelial function (measured by isometric tension recording, efficacy in %) inversely correlates with mitochondrial ROS formation (measured by L‐012‐derived chemiluminescence [peroxynitrite, superoxide or hydrogen peroxide formation] in isolated mitochondria; expressed as RLU/min) in aging mice with antioxidant enzyme deficiencies (mitochondrial aldehyde dehydrogenase [ALDH‐2]−/− and MnSOD+/−). ALDH‐2 deficiency leads to increased carbonyl stress since the enzyme is a major sink of toxic aldehydes. MnSOD deficiency increases mitochondrial superoxide levels and leads to increased cardiac fibrosis and impaired vascular function under oxidative stress conditions. RLU, relative light units. Retraced from original data of Wenzel et al. and Daiber, Cardiovasc. Res. 2008 (Wenzel et al., 2008c).
Figure 4
Figure 4
Crosstalk between different sources of ROS and RNS (mitochondria, NADPH oxidases, xanthine oxidase and NO synthase). Xanthine oxidase (XO) originates from oxidative stress‐mediated conversion of the xanthine dehydrogenase via oxidation of critical thiols in cysteine535/992. NO synthases (mainly eNOS) are uncoupled upon oxidative depletion of tetrahydrobiopterin (BH4), S‐glutathionylation (−SSG) and other redox switches (see Figure 2). Mitochondrial superoxide/hydrogen peroxide formation may is triggered by oxidative stress from all ROS sources (including other damaged/activated mitochondria) via redox‐activation of PKC, MAPK, other kinase pathways and potential involvement of redox‐sensitive mitochondrial ATP‐sensitive potassium channels (mtKATP) with subsequent p66Shc, monoamine oxidase (MAO), respiratory complex activation or impairment of mitochondrial antioxidant defence. Mitochondrial superoxide/hydrogen peroxide is released to the cytosol via mitochondrial pores and channels (e.g. redox‐sensitive mitochondrial permeability transition pore (mPTP), inner membrane anion channel (IMAC) or aquaporins) or by diffusion due to increased mitochondrial permeability under pro‐inflammatory conditions. In the cytosol these species (along with released calcium) cause activation of redox‐sensitive protein kinases (PKC) and tyrosine kinases (cSrc) with subsequent activation of NADPH oxidases and amplification of the cellular oxidative stress. Modified from Daiber, Biochim. Biophys. Acta 2010 (Daiber, 2010). With permission of Elsevier. Copyright 2010.
Figure 5
Figure 5
Redox crosstalk between mitochondria and NADPH oxidase through reactive oxygen and nitrogen species. Based on our own and others observations, we favour the crosstalk between mitochondria and Nox2 (in white blood cells and the vasculature). Mitochondrial superoxide/hydrogen peroxide formation is induced by the aging process, nitroglycerin treatment, hypoxia/reperfusion or stimulated by extramitochondrial ROS causing redox‐activation of PKC, MAPK, other kinase pathways and potential involvement of redox‐sensitive mitochondrial ATP‐sensitive potassium channels (mtKATP) with subsequent p66Shc, monoamine oxidase (MAO), respiratory complex activation or impairment of mitochondrial antioxidant defence. Evidence for involvement of redox‐sensitive mitochondrial permeability transition pore (mPTP) is based on its pharmacological and genetic inhibition and normalization of the phenotype in various disease and pharmacological complications (e.g. eNOS S‐glutathionylation and uncoupling). Previous data on redox‐sensitive cysteine residues in cyclophilin D, a regulatory subunit of the mPTP support opening of the pore under oxidative stress conditions. Other redox‐regulated parts of the pore may constitute of the voltage‐dependent anion channel (VDAC) and adenine nucleotide translocase (ANT) or it may be even formed by dimerised mitochondrial ATP synthase in the inner mitochondrial membrane. Direct angiotensin‐II (AT‐II) triggered mitochondrial calcium uptake could contribute to mPTP opening. Other routes for release of mitochondrial superoxide/hydrogen peroxide may involve the inner membrane anion channel (IMAC), aquaporins or diffusion due to increased mitochondrial permeability under pro‐inflammatory conditions. The contribution of mKATP channels to this crosstalk is so far only based on inhibitors and openers of mKATP channels (e.g. 5‐HD, glibenclamide and diazoxide). Evidence for involvement of redox‐sensitive protein kinases (PKC, cSrc) is based on pharmacological and genetic inhibition of these kinases and inhibition of the crosstalk and rescue of the adverse effects. The role of mitochondrial superoxide/hydrogen peroxide and calcium in this process was also shown by specific scavengers and chelators as well as MnSOD deficiency for mitochondrial superoxide importance. PTP means protein tyrosine phosphatase. This scheme includes the concepts of previous work on “ROS‐induced ROS” (for review see (Brandes, 2005; Di Lisa and Bernardi, 2006; Daiber, 2010; Dikalov, 2011; Nickel et al., 2014; Schulz et al., 2014; Zorov et al., 2014)). Modified from Kröller‐Schön et al. and Daiber, Antioxid. Redox Signal. 2014 (Kroller‐Schon et al., 2014). With permission of Mary Ann Liebert, Inc. Copyright 2014.
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