Oxidative stress and mitochondrial dysfunction in sepsis
2011; Elsevier BV; Volume: 107; Issue: 1 Linguagem: Inglês
10.1093/bja/aer093
ISSN1471-6771
Autores Tópico(s)Intensive Care Unit Cognitive Disorders
ResumoSepsis-related organ dysfunction remains the most common cause of death in the intensive care unit (ICU), despite advances in healthcare and science. Marked oxidative stress as a result of the inflammatory responses inherent with sepsis initiates changes in mitochondrial function which may result in organ damage. Normally, a complex system of interacting antioxidant defences is able to combat oxidative stress and prevents damage to mitochondria. Despite the accepted role that oxidative stress-mediated injury plays in the development of organ failure, there is still little conclusive evidence of any beneficial effect of systemic antioxidant supplementation in patients with sepsis and organ dysfunction. It has been suggested, however, that antioxidant therapy delivered specifically to mitochondria may be useful. Sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit (ICU), despite advances in healthcare and science. Marked oxidative stress as a result of the inflammatory responses inherent with sepsis initiates changes in mitochondrial function which may result in organ damage. Normally, a complex system of interacting antioxidant defences is able to combat oxidative stress and prevents damage to mitochondria. Despite the accepted role that oxidative stress-mediated injury plays in the development of organ failure, there is still little conclusive evidence of any beneficial effect of systemic antioxidant supplementation in patients with sepsis and organ dysfunction. It has been suggested, however, that antioxidant therapy delivered specifically to mitochondria may be useful. Editor’s key points•Sepsis-induced organ failure is associated with oxidative stress and mitochondrial damage.•Reactive oxygen species are produced as a normal consequence of energy production.•Antioxidants protect mitochondria but may become overwhelmed in sepsis.•Antioxidants acting specifically in mitochondria may be of benefit in patients with sepsis. •Sepsis-induced organ failure is associated with oxidative stress and mitochondrial damage.•Reactive oxygen species are produced as a normal consequence of energy production.•Antioxidants protect mitochondria but may become overwhelmed in sepsis.•Antioxidants acting specifically in mitochondria may be of benefit in patients with sepsis. With a mortality rate of around 25% for uncomplicated sepsis, rising to 80% in those patients who go on to develop multiple organ failure, sepsis is the most common cause of mortality in an intensive care unit and the incidence is increasing.1Marshall JC Vincent JL Guyatt G et al.Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum.Crit Care Med. 2005; 33: 1708-1716doi:10.1097/01.CCM.0000174478.70338.03Crossref PubMed Scopus (115) Google Scholar During sepsis-induced organ failure, the inflammatory response and ensuing oxidative stress induce changes in mitochondria which result in mitochondrial dysfunction and cell death. The inner membrane of mitochondria has a large surface area which is impermeable and contains the enzymes involved in oxidative phosphorylation–energy production from oxygen. Production of energy as ATP takes place via a flow of electrons passed along the five molecular complexes of the electron transport chain. The electron transfer results in reciprocal transfer of protons, creating the mitochondrial membrane potential. As part of this process, reactive oxygen species (ROS) are generated as by-products of the incomplete four-electron reduction of molecular oxygen to water, the final electron acceptor in the process of ATP production (Fig. 1). One by one electron reduction of oxygen from escaped electrons means that as much as 1% of oxygen is converted to ROS. The term ROS includes molecules with an unpaired electron, called free radicals, such as superoxide anion, and also strong oxidizing agents such as hydrogen peroxide. ROS can react avidly with the surrounding molecules in an indiscriminate fashion and so are both highly reactive and short-lived, and can be damaging if not controlled (Fig. 2). The electron transport chain of mitochondria is the major source of intracellular ROS in the cell and mitochondria are also a major target for damage by ROS.2Murphy MP How mitochondria produce reactive oxygen species.Biochem J. 2009; 417: 1-13doi:10.1042/BJ20081386Crossref PubMed Scopus (5238) Google Scholar 3Turrens JF Mitochondrial formation of reactive oxygen species.J Physiol. 2003; 552: 335-344doi:10.1113/jphysiol.2003.049478Crossref PubMed Scopus (3575) Google Scholar ROS have essential roles in cell signalling and their activity is normally tightly regulated by a collaborative interacting network of antioxidants. Production of ROS by mitochondria is important for normal cellular function and survival and it should be remembered that mitochondria have other roles other than energy production, for example, in various cell signalling pathways and calcium and iron homeostasis.4Kaakar P Singh BK Mitochondria: a hub of redox activities and cellular distress control.Mol Cell Biochem. 2007; 305: 235-253Crossref PubMed Scopus (204) Google ScholarFig 2Overview of mitochondrial ROS production. ROS production within mitochondria can lead to oxidative damage to mitochondrial proteins, membranes, and mtDNA. Mitochondrial oxidative damage leads to the release of cytochrome c (cyt c) into the cytosol resulting in apoptosis. Increased permeability makes the inner membrane permeable to small molecules. Mitochondrial ROS are also important in cell signalling pathways which modulate several cellular functions. Figure reproduced with permission, from Murphy MP (2009).2Murphy MP How mitochondria produce reactive oxygen species.Biochem J. 2009; 417: 1-13doi:10.1042/BJ20081386Crossref PubMed Scopus (5238) Google Scholar © The Biochemical Society.View Large Image Figure ViewerDownload (PPT) In addition to producing ROS, the mitochondrial respiratory chain can produce nitric oxide, which itself has an unpaired electron and is therefore a free radical, and other nitric oxide by-products called reactive nitrogen species (RNS). For example, the highly toxic molecule peroxynitrite is formed from the reaction of nitric oxide with superoxide anion. Production of nitric oxide is increased during sepsis by de novo synthesis of the inducible form of type II nitric oxide synthase (NOS). Although superoxide anion is quickly converted to hydrogen peroxide and then water under the action of the endogenous antioxidant enzyme systems, the reaction between superoxide anion and nitric oxide to form peroxynitrite is far more rapid. Peroxynitrite is thought to account for most of the cytotoxic actions of nitric oxide. Nitric oxide has several vital physiological roles, but RNS can have detrimental effects through oxidation, nitrosylation, or nitration of various cellular targets, including proteins, nucleic acids, and endogenous antioxidants such as glutathione.5Brown GC Borutaite V Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols.Biochim Biophys Acta. 2004; 1658: 44-49doi:10.1016/j.bbabio.2004.03.016Crossref PubMed Scopus (288) Google Scholar It has been proposed that a mitochondrial form of NOS exists, although this is by no means certain6Ghafourifar P Cadenas E Mitochondrial nitric oxide synthase.Trends Pharmacol Sci. 2005; 26: 190-195doi:10.1016/j.tips.2005.02.005Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar 7Lacza Z Pankotai E Csordás A et al.Mitochondrial NO and reactive nitrogen species production: does mtNOS exist?.Nitric Oxide. 2006; 14: 162-168doi:10.1016/j.niox.2005.05.011Crossref PubMed Scopus (99) Google Scholar and so this review will specifically address mitochondrial ROS and the mitochondrial antioxidant protection mechanisms. When antioxidant defences are overwhelmed, oxidative stress results, which can cause significant damage to lipids, proteins, and nucleic acids, both within mitochondria and cells (Fig. 2). For example, peroxidation of the mitochondrial lipid cardiolipin, which is present in the inner mitochondrial membrane and is important for energy metabolism, leads to dissociation of cytochrome c and causes reduced ATP production, and even more ROS production.3Turrens JF Mitochondrial formation of reactive oxygen species.J Physiol. 2003; 552: 335-344doi:10.1113/jphysiol.2003.049478Crossref PubMed Scopus (3575) Google Scholar 4Kaakar P Singh BK Mitochondria: a hub of redox activities and cellular distress control.Mol Cell Biochem. 2007; 305: 235-253Crossref PubMed Scopus (204) Google Scholar 8Droge W Free radicals in the physiological control of cell function.Physiol Rev. 2002; 82: 47-95Crossref PubMed Scopus (7493) Google Scholar 9James AM Murphy MP How mitochondrial damage affects cell function.J Biomed Sci. 2002; 9: 475-487doi:10.1007/BF02254975Crossref PubMed Google Scholar The endogenous antioxidant systems themselves can also be affected by oxidative stress via oxidation and peroxidation of the component enzymes. In addition, mitochondrial DNA (mtDNA) is also a target for damage since it is close to the electron transport chain.10Ozawa T Mitochondrial genome mutation in cell death and ageing.J Bioenerg Biomembr. 1999; 31: 377-390doi:10.1023/A:1005479920097Crossref PubMed Scopus (34) Google Scholar mtDNA encodes for several polypeptides plus transfer RNA species and ribosomal RNA species that are vital for electron transport and energy generation. All of the mtDNA encodes expressed genes, unlike genomic DNA which contains many non-coding sequences and thus the potential is higher for functional mutations.11Van-Remmen H Richardson A Oxidative damage to mitochondria and ageing.Exp Gerontol. 2001; 36: 957-968doi:10.1016/S0531-5565(01)00093-6Crossref PubMed Scopus (204) Google Scholar Oxidative stress-mediated damage to mtDNA can lead to a cycle of ROS production and further mtDNA damage; in other words, a perpetual cycle of ROS production facilitated by ROS-induced ROS release. This cycle of mtDNA damage with loss of function of electron transport enzymes and more ROS generation where the antioxidant systems are completely overwhelmed and eventually cell death occurs is known as the ‘mitochondrial catastrophe hypothesis’ or ‘toxic oxidative stress’.12Fariss MW Chan CB Patel M Van Houten B Orrenius S Role of mitochondria in toxic oxidative stress.Mol Interv. 2005; 5: 94-111doi:10.1124/mi.5.2.7Crossref PubMed Scopus (238) Google Scholar Although normally the inner membrane is impermeable, mitochondria can undergo the so-called permeability transition resulting in activation of the caspase cascade, via the release of cytochrome c and apoptosis-inducing factor, which ultimately results in apoptosis or programmed cell death. Mitochondrial membrane permeability transition is a critical point for apoptosis. The permeability transition can be initiated by oxidative stress, nitric oxide, calcium overload, or apoptotic protein upregulation, but regardless of the initiating mechanism, increased mitochondrial permeability is the endpoint for the cell since there is no return after the release of caspase activators such as cytochrome c. See Figure 2 for an overview of mitochondrial ROS production and its consequences. Several interacting endogenous antioxidant systems exist within mitochondria to protect against damage by ROS. This network of antioxidant defence systems is tightly regulated and consists of a combination of enzyme and non-enzyme pathways. These include manganese superoxide dismutase (MnSOD), the glutathione (GSH) and thioredoxin (TSH) systems, peroxiredoxins, sulphiredoxins, cytochrome c, peroxidase, and catalase.13Zhang H Go YM Jones DP Mitochondrial thioredoxin-2/peroxiredoxin-3 system functions in parallel with mitochondrial GSH system in protection against oxidative stress.Arch Biochem Biophys. 2007; 465: 119-126doi:10.1016/j.abb.2007.05.001Crossref PubMed Scopus (112) Google Scholar 14Jones DP Radical-free biology of oxidative stress.Am J Physiol Cell Physiol. 2008; 295: C849-C868doi:10.1152/ajpcell.00283.2008Crossref PubMed Scopus (854) Google Scholar Superoxide anion generated within mitochondria is unable to cross the mitochondrial membrane very easily and so is converted to hydrogen peroxide by the action of MnSOD. Although hydrogen peroxide is able to diffuse out of mitochondria for metabolism by catalase, in all but heart mitochondria, this occurs within peroxisomes, not mitochondria. The main system of removal is through the oxidation of reduced mitochondrial GSH (mGSH), catalysed by mGSH peroxidase-1 with recycling back to reduced glutathione catalysed by glutathione reductase, which all take place within mitochondria.15Watabe S Hiroi T Yamamoto Y et al.SP-22 is a thioredox-independent peroxide reductase in mitochondria.Eur J Biochem. 1997; 249: 52-60doi:10.1111/j.1432-1033.1997.t01-1-00052.xCrossref PubMed Scopus (132) Google Scholar Oxidation of mitochondrial thioredoxin-2 (TRX-2) with its associated enzymes peroxiredoxin-3 and thioredoxin reductase-2 is also important.16Patenaude A Ven Murthy MR Mirault ME Mitochondrial thioredoxin system—effects of TrxR2 overexpression on redox balance, cell growth, and apoptosis.J Biol Chem. 2004; 279: 27302-27314doi:10.1074/jbc.M402496200Crossref PubMed Scopus (97) Google Scholar Although GSH is the most abundant antioxidant in mitochondria, the TRX-2 system has been reported to be more efficient at maintaining mitochondrial proteins in a reduced state compared with mGSH.13Zhang H Go YM Jones DP Mitochondrial thioredoxin-2/peroxiredoxin-3 system functions in parallel with mitochondrial GSH system in protection against oxidative stress.Arch Biochem Biophys. 2007; 465: 119-126doi:10.1016/j.abb.2007.05.001Crossref PubMed Scopus (112) Google Scholar However, when oxidative stress is at a relatively low level, both systems keep hydrogen peroxide levels in check and have well-defined roles. 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