Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I

Chouchani, Edward T.; Methner, Carmen; Nadtochiy, Sergiy M.; Logan, Angela; Pell, Victoria R.; Ding, Shuzhe; James, Andrew M.; Cochemé, Helena M.; Reinhold, Johannes; Lilley, Kathryn S.; Partridge, Linda; Fearnley, Ian M.; Robinson, Alan J.; Hartley, Richard C.; Smith, Robin A.J.; Krieg, Thomas; Brookes, Paul S.; Murphy, Michael P.

doi:10.1038/nm.3212

Cited by 555 publications

(601 citation statements)

References 47 publications

(58 reference statements)

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“…More particularly, the oxidation of thiol functions and cysteine residues, which is an important mechanism regulating protein structure, was reported on proteins described to be involved in the formation of the pore or in the regulation of its opening, such as ANT (Costantini et al., 2000; Halestrap, Woodfield, & Connern, 1997), CypD (Nguyen et al., 2011), ATP synthase (Wang, Murray, Chung, & Van Eyk, 2013), or complex I of the respiratory chain (Chouchani et al., 2013). As both glutathione and cysteine systems become oxidized during aging (Go & Jones, 2017), this can contribute to mPTP opening.…”

Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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“…NO inhibits mitochondrial complex I by S-nitrosation (or S-nitrosylation) of cysteines, which subsequently prevents damage during IR injury [47]. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion, thereby decreasing ROS production, oxidative damage, and tissue necrosis [48].…”

Section: Nitric Oxide In Myocardial Ischemia-reperfusion Injurymentioning

confidence: 99%

Real-Time Monitoring of Nitric Oxide Dynamics in the Myocardium: Biomedical Application of Nitric Oxide Sensor

Lee¹,

Lee²,

Park³

2017

Nitric Oxide Synthase - Simple Enzyme-Complex Roles

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Nitric oxide (NO) is an important physiological mediator that regulates a wide range of cellular processes in many tissues. Therefore, the accurate and reliable measurement of physiological NO concentration is essential to the understanding of NO signaling and its biological role. Most methods used for NO detection are indirect including spectroscopic approaches such as the Griess assay for nitrite and detection of methemoglobin after NO reaction with oxyhemoglobin. These methods cannot accurately reflect the changes in NO concentration in vivo and in real time. Therefore, direct methods are necessary for investigating biological process and diseases related to NO in biological conditions. There is a growing interest in the development of electrochemically based sensors for direct, in vivo, and real-time monitoring of NO. Electrochemical methods offer simplicity, good sensitivity, high selectivity, fast response times, and long-term calibration stability compared to other techniques including electron paramagnetic resonance, chemiluminescence, and fluorescence. In this article, we present real-time NO dynamics in the myocardium during myocardial ischemia-reperfusion (IR) utilizing electrochemical NO microsensor. And applications of electrochemical NO sensor for the evaluation of cardioprotective effects of therapeutic treatments such as drug administration and ischemic preconditioning are reviewed.

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“…Various mitochondrial proteins are susceptible to reversible and irreversible redox modifications, allowing local regulation of their function and/or affecting pathological processes. For instance, reversible S-nitrosylation of Complex I at Cys39 of the ND3 subunit decreased ROS production, oxidative damage and tissue necrosis and thereby protected against injury during cardiac ischemia-reperfusion in vivo (Chouchani et al 2013). Although a full understanding is still lacking, net mitochondrial morphology, a result of continuous fusion and fission events, appears to be linked to mitochondrial function, ROS generation and redox state as well ).…”

Section: Mitochondria Are Prime Sources and Targets Of Rosmentioning

confidence: 99%

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Sieprath

Corne

Willems

et al. 2016

Advances in Anatomy, Embryology and Cell Biology

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Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-content microscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells. Principles of intracellular ROS generation and removalReactive oxygen species (ROS) are small, short-lived derivatives of molecular oxygen (O 2 ) of radical and non-radical nature (Halliwell and Gutteridge 2007 • ), nitrate radical (NO 3 • ) and many other nitrogen derivatives. ROS were originally described as molecular constituents of the defense system of phagocytic cells, but it has become clear that besides their damaging properties, they also function as signaling molecules and mediate a variety of other cellular responses including cell proliferation, differentiation, gene expression and migration (Lambeth 2004;Bartz and Piantadosi 2010). Intracellular ROS metabolismROS can be generated at various sites in the cell (Fig. 1A). This can be either deliberately, e.g. by NADPH oxidases (NOX), or as a byproduct, e.g. during normal cellular respiration in mitochondria (Babior 1999;Turrens 2003;Murphy 2009). The NOX family of NADPH oxidases (NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2) are proteins that transport electrons (e -) from NADPH across biological membranes (plasma or endomembranes) (Bedard and Krause 2007;Dupre-Crochet et al. 2013). The activation mechanisms and tissue distribution of the isoforms differ but they all use O 2 as e --acceptor, producing O 2•-. Through ROS generation, they play a role in many cellular processes including host defense, regulation of gene expression and cell differentiation (Bedard and Krause 2007). Despite their sometimes significant contribution to the global ROS pools, NOX are not the predominant source of intracellular ROS. Mitochondria are considered the major culprit, in particular under pathological conditions. Mitochondrial ROS are generated as a byproduct of the oxidative phosphorylation (OXPHOS, cf. below). Irrespective of its source, ROS production generally sta...

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Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I

Cited by 555 publications

References 47 publications

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria and aging: A role for the mitochondrial transition pore?

Real-Time Monitoring of Nitric Oxide Dynamics in the Myocardium: Biomedical Application of Nitric Oxide Sensor

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

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