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Mechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage

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Official websites use. Share sensitive information only on official, secure websites. To whom all correspondences should be addressed: Dr. Despite numerous reports about the acute and sub-chronic toxicities caused by MDMA 3,4-methylenedioxymethamphetamine, ecstasy , the underlying mechanism of organ damage is poorly understood. Because of the extensive reviews on MDMA-mediated oxidative stress and tissue damage, we specifically focus on the mechanisms and consequences of oxidative-modifications of mitochondrial proteins, leading to mitochondrial dysfunction. We briefly describe a method to systematically identify oxidatively-modified mitochondrial proteins in control and MDMA-exposed rats by using biotin- N -maleimide biotin-NM as a sensitive probe for oxidized proteins. We also describe various applications and advantages of this Cys-targeted proteomics method and alternative approaches to overcome potential limitations of this method in studying oxidized proteins from MDMA-exposed tissues. Finally we discuss the mechanism of synergistic drug-interaction between MDMA and other abused substances including alcohol ethanol as well as application of this redox-based proteomics method in translational studies for developing effective preventive and therapeutic agents against MDMA-induced organ damage. Recent epidemiological studies indicate that 3,4-methylenedioxymethamphetamine MDMA, Ecstasy 1 , a synthetic derivative of amphetamine with a range of psychotropic actions, is widely abused by mostly young people during rave parties large social gatherings characterized by dancing and loud music. Repeated usages of MDMA pose significant public health and social problems in the United States and other countries \[ 1 — 3 \]. In fact, acute or sub-chronic exposure to MDMA alone or in combination with other abused substances e. Acute MDMA toxicity can lead to myocardial infarction and arrhythmia often accompanied with tachycardia, hypertension, and hyperthermia, all of which usually precede disseminated intravascular coagulation, rhabdomyolysis, and multiple organ failure or death \[ 8 , 9 \]. The life threatening clinical manifestations of MDMA toxicity also include acute hepatic damage \[ 10 — 12 \], hyponatremia, and rhabdomyolysis-induced renal failure \[ 13 — 15 \]. In addition, MDMA is known to interfere with endocrine, gonadal, and immune functions \[ 16 — 18 \]. In the brain, MDMA was shown to deplete serotonergic neurotransmitter and cause neurodegeneration through serotonin transporter action, nitric oxide and peroxynitrite, and formation of neurotoxic MDMA metabolites \[ 19 — 21 \]. Although MDMA-mediated toxicities are well-established, the general public does not seem to fully appreciate the adverse consequences associated with MDMA usage. In fact, MDMA is a major cause of liver injury in people under the age of 25 years \[ 12 \]. All these points suggest an urgent need to educate the public about the toxicities of MDMA. Although many reports have demonstrated MDMA-induced organ damage \[ 11 — 13 \], the underlying mechanism accounting for tissue toxicity is poorly understood. Various factors contribute to the extent of MDMA-induced injury to different tissues. Quinones are highly redox-active molecules that can undergo the following pathways: a a redox cycle producing semiquinones radicals, leading to the generation of reactive oxygen species ROS \[ 28 , 29 \]; b irreversible 1,4-intramolecular cyclization with subsequent formation of aminochromes \[ 25 \]; c conjugation with reduced glutathione GSH to form a glutathionyl adduct that can further react with GSH and protein thiols, leading to GSH depletion \[ 27 , 30 \]; and d formation of MDMA-protein adducts, leading to inactivation of the target proteins \[ 31 \]. It is also believed that other tissues including brain, heart and kidney would be affected in a similar mechanism following the metabolism of MDMA \[ 32 , 33 \]. Since antioxidant defense systems become severely impaired upon MDMA exposure, administration of small molecule antioxidants such as N -acetylcysteine and ascorbic acid or over-expression of antioxidant enzymes like superoxide dismutase, can potentially neutralize the toxic effects of MDMA \[ 27 , 34 \]. Depletion of GSH levels following MDMA exposure correlates with increased oxidative stress accompanied with lipid peroxidation, DNA damage, protein oxidation and cell damage \[ 27 , 29 , 35 , 36 \]. These changes promote oxidative modifications of many mitochondrial proteins, resulting in their inactivation followed by mitochondrial dysfunction and tissue damage after MDMA exposure. Interruption of the mitochondrial electron transport system would lead to increased leakage of ROS including hydrogen peroxide from the mitochondrial respiratory chain, as demonstrated in neurodegenerative diseases \[ 43 \] or after exposure to toxic agents \[ 41 , 42 , 44 \]. Moreover, MDMA exposure increases nitrosative stress \[ 37 , 38 , 44 \]. The modification of these macromolecules has deleterious effects on their physiological functions. Peroxynitrite is known to nitrate Tyr residues \[ 46 \] as well as S -nitrosylate Cys residues in many proteins \[ 47 \]. Production of peroxynitrite after MDMA exposure likely leads to the oxidative modifications of some mitochondrial complex proteins, resulting in their inhibition, as described \[ 48 , 49 \]. The inactivation of certain mitochondrial proteins likely contributes to mitochondrial dysfunction and organ damage especially in the presence of another co-morbidity factor such as alcohol ethanol and cocaine. Despite many reports about MDMA-mediated oxidative stress and lipid peroxidation \[ 36 , 44 , 50 \], the identities of the oxidatively-modified proteins in MDMA-exposed tissues have not been reported. To our knowledge, few systematic proteomic analyses have been performed to investigate the changes in protein expression or identify oxidatively-modified proteins in MDMA-exposed tissues. Based on the increased oxidative stress following MDMA exposure, we hypothesized that oxidative modifications of certain mitochondrial proteins lead to inhibition of their activities, resulting in mitochondrial dysfunction and ultimately contributing to MDMA-mediated organ damage. To test this hypothesis and to elucidate the mechanism of mitochondrial dysfunction, we systematically analyzed the oxidatively-modified mitochondrial proteins in MDMA-exposed tissues. Characterization of the oxidatively-modified proteins accompanied with biochemical analysis would aid our understanding of the molecular mechanisms of mitochondrial dysfunction and tissue injury associated with MDMA. In this review, we briefly describe our systematic identification of oxidatively-modified mitochondrial proteins using the redox-based Cys-targeted proteomic method that was recently developed in this laboratory and the implications of our findings in the understanding the mechanism of MDMA- induced liver damage \[ 51 — 54 \]. We also discuss the application of this redox-based proteomics method for studying oxidized proteins in other sub-cellular organelles of various tissues as well as the advantages and limitations of this method. Although our studies have focused on hepatic proteins, our approach should be amenable for characterizing the mechanisms of organ damage in other tissues. We specifically studied the oxidative modifications of Cys residues in proteins because of the availability of Cys-specific reagents such as N -ethylmaleimide and biotin- N -maleimide biotin-NM. As described in our reports \[ 44 , 51 \], the oxidatively-modified protein thiols in MDMA-exposed rat livers versus controls were labeled with biotin-NM and then detected by immunoblot analysis with the monoclonal antibody against biotin. To further determine the identity of each protein, biotin-NM-labeled oxidized proteins from controls and MDMA-exposed tissues were purified by streptavidin-agarose beads. Densities of both gels representing the oxidized proteins in control animals or MDMA-exposed rats were adjusted for comparable exposure levels of an internal control protein in 2 different gels. Under these comparable conditions, we observed that the intensity and number of oxidized mitochondrial proteins were increased in MDMA-exposed tissues than those of control \[ 44 \]. Mass spectral analysis of the protein spots excised from the 2-D gels revealed that many mitochondrial proteins were oxidatively modified in MDMA-exposed rat livers. The list of the oxidized mitochondrial proteins is summarized in Fig. These proteins are involved in: protein folding chaperone proteins , oxidative phosphorylation, energy production, anti-oxidant defense, fat metabolism, electron transport, etc. Inactivation of these enzymes correlated with increased hydrogen peroxide, decreased ATP level, accumulation of lipid peroxides such as malondialdehyde MDAL , and triglyceride fat accumulation, respectively \[ 44 \]. Moreover, mitochondrial dysfunction with decreased activities of mitochondrial proteins correlated with biochemical measurements of plasma transaminase activities and histological examinations of the liver specimens \[ 44 \]. Although we did not measure the activities of all of the proteins listed in Fig. Summary of oxidized mitochondrial proteins in MDMA-exposed rat livers. Treated rats were euthanized 12 h after the last dose of MDMA and oxidized mitochondrial proteins were analyzed, as described \[ 44 \]. Oxidized mitochondrial proteins are summarized under different functions. Although we showed that many mitochondrial proteins were oxidatively-modified in MDMA-exposed tissues, we believe that the actual number of oxidized proteins could be much higher since some of the mitochondrial proteins, expressed in small quantities, might not be detected by the current method. In addition, some of the oxidized or nitrated proteins could be rapidly degraded \[ 55 , 58 , 59 \] and thus could not be detected by our analysis. These data indicate that oxidatively-modified parent proteins were spontaneously broken into smaller fragments \[ 55 \] or subjected to proteolytic degradation \[ 58 , 59 \]. However, no detection by this Cys-targeted proteomics approach does not necessarily mean no or little oxidative modification of a certain protein. In fact, oxidation of a certain protein, especially expressed in small quantity and thus not detected by this technique, can be demonstated by immunoblot analysis with an antibody against S-NO-Cys or glutathione for detection of mixed disulfides after the target protein is immunoprecipitated with a specific antibody against it, as discussed below. The redox-based, Cys-targeted approach using biotin-NM, as we originally described \[ 51 — 54 \], exhibited a major advantage in detecting subtle increments in the amounts of oxidatively-modified proteins over the previously existing methods of using biotin-conjugated iodoacetamide BIAM \[ 60 \], 4-iodobutyl-triphenylphosphonium \[ 61 \], or isotope-coded affinity tag ICAT reagent \[ 62 \], mainly because the levels of oxidized proteins detected with these reagents e. Furthermore, the biotin-switch method using biotin-NM as a probe does not need special reagents as stated \[ 51 \]. This is in contrast to the requirement of special reagents such as a specific antibody to 4-iodobutyltriphenyl-phosphonium \[ 61 \] or a cysteine-specific ICAT reagent \[ 62 \]. All reagents used in this method are available commercially and easy to obtain. Many proteomics approaches including 2-D Fluorescence Difference Gel Electrophoresis 2-D-DIGE have been recently developed to efficiently determine different levels of protein expression in a variety of samples e. Although this newly-developed 2-D DIGE method may allow us to evaluate different levels of protein expression following MDMA exposure, it does not always predict functional alterations of certain proteins due to their post-translational modifications. In fact, many proteins are known to be functionally altered i. Based on pre-existing literature and our data \[summarized in Fig. Inhibition of this enzyme was experimentally confirmed by comparing the activities in MDMA-exposed tissues relative to control \[ 44 \]. In fact, this redox-related proteomics method can be used to systematically identify oxidatively-modified proteins in different sub-cellular organelles \[e. Based on the MDMA-mediated oxidative stress, we also expected that an increased number of oxidized cytosolic proteins would be identified in MDMA-exposed tissues. Consistent with this prediction, our unpublished, preliminary results showed that the number and intensity of oxidized proteins in the cytoplasm are significantly increased in MDMA-exposed liver compared to those of controls. Moreover, cytosolic peroxiredoxin, involved in anti-oxidant defense, was oxidized in MDMA-exposed rat tissues, as it was in ethanol-exposed hepatoma cells and mouse livers \[ 52 \]. These stress-activated protein kinases may contribute to apoptosis with concomitant release of mitochondrial cytochrome c into cytoplasm and caspase activation \[ 72 \]. This redox-based method can also be used for future translational research in treating MDMA-related behavioral and pathological damage. Understanding of the molecular mechanisms of MDMA-induced toxicities would be very important in developing efficient preventive or therapeutic agents for MDMA-abused people. The redox-based Cys-targeted approach described here can be also used to evaluate or monitor the efficacy of certain beneficial agents against MDMA-exposed tissue injury by studying the pattern of oxidatively-modified proteins before and after treatment with the beneficial agent. Based on our recent data \[ 75 \], we expect that the levels of oxidatively-modified proteins in MDMA-treated samples would be significantly decreased when the animals are pretreated with certain anti-oxidants or other cell protective agents. However, our expectations need to be experimentally supported in the future. Despite many advantages and application potential, this Cys-targeted proteomics approach also possesses some limitations. Common to all proteomics methods including 2-D DIGE method \[ 63 , 64 \], the Cys-targeted redox proteomics approach only allows us to detect oxidatively-modified proteins expressed in large quantities, as we originally described \[ 51 \]. For instance, it is unlikely that we can detect oxidative modifications of certain enzymes or transcription factors that are expressed in very low quantities, although these proteins may contain Cys residues that can be oxidatively-modified following MDMA exposure. The failure to detect these proteins could be simply due to their low levels of expression relative to other proteins in the specific tissues of interest. However, despite this limitation, it is possible to successfully demonstrate oxidative modifications of these proteins by immunoprecipitation with a specific antibody against each target protein and then immunoblot analysis with a specific antibody against S-NO-Cys or glutathione for detecting mixed disulfides. This alternative approach should be accompanied by the measurements of the specific enzyme activity or protein levels to further confirm functional implications of their oxidative modifications. For instance, it was shown that MDMA inhibits the activity of tryptophan hydroxylase TPH , the initial and rate limiting enzyme in the biosynthesis of the neurotransmitter serotonin, through elevated peroxynitrite, which can nitrate Tyr residues and S -nitrosylate Cys residues in many proteins \[ 46 , 47 \]. This mechanism provides one potential cause of serotonin depletion and neuropsychiatric behavioral deficits observed after MDMA usage, although many other mechanisms probably exist. Tyrosine hydroxylase, the first and rate-limiting enzyme in the biosynthesis of the neurotransmitter dopamine, was also inhibited by a similar mechanism of peroxynitrite-mediated S -nitrosylation of Cys residues \[ 77 \], although this enzyme can be inhibited through nitration of critical Tyr residues \[ 78 \]. In case of transcription factors, one can measure the mRNA and protein levels of their down-stream targets. It is expected that these critical enzymes or many transcription factors may not be detected by the Cys-targeted analysis due to their low levels of expression compared to other proteins expressed in large amounts. Another limitation of the redox-related Cys-targeted proteomics approach is that Cys residues of various proteins can be modified by many different reactions, as discussed \[ 79 \]. Furthermore, Cys residues can undergo adduct formation with lipid peroxides such as MDAL, which can be elevated under oxidative stress \[ 81 , 82 \]. In fact, MDMA exposure increased the levels of lipid peroxides \[ 44 , 83 \]. In many cases, the activities of certain proteins are inhibited although their levels are not altered, suggesting that the catalytic and other critical Cys residues of these proteins are likely oxidatively-modified or conjugated with reactive MDMA metabolites, as reviewed \[ 84 \]. The covalent modifications of Cys residues in the latter cases can be demonstrated by measuring the enzyme activity after incubation with DTT, a strong reducing agent. If the suppressed enzyme activities are recovered by the addition of DTT \[ 51 — 54 \], the critical Cys residue s of target proteins are likely to be oxidatively modified to sulfenic acid, S -nitrosylation, or disulfides including mixed disulfides with glutathione. If the catalytic activities are not restored even after incubation with DTT, this likely represents the irreversible, covalent modifications e. Alternatively, other amino acid residues e. Therefore, it is advised to consider many possible routes of oxidative modifications in analyzing the data from MDMA-exposed tissues. In addition to damage to neuronal tissues which were studied extensively, MDMA can cause many other peripheral tissues such as heart, liver, kidney, testes, etc. Similar to liver damage, MDMA and its metabolites are also known to damage kidney during their excretion through the kidney. MDMA-induced rhabdomyolysis necrosis of myocytes from a rapid rise in cellular calcium , which can lead to myoglobin deposition in the kidney, along with extreme dehydration and electrolyte imbalances may also contribute to acute and chronic renal failure \[ 13 — 15 , 86 \]. MDMA also interferes with endocrine function, altering the levels of corticotrophin i. Since the extra-hepatic tissues contain very low levels of MDMA-metabolizing P isozymes compared to the liver , MDMA metabolites produced in the liver are likely to be responsible for the toxic effects of MDMA in the brain, heart and other peripheral tissues. This notion was supported by the fact that direct administration of MDMA into the brain or heart did not cause tissue damage \[ 32 , 33 \]. Therefore, it would be of interest to determine which proteins are oxidatively-modified and how the oxidized proteins correlate with the degree of tissue damage in these extra-hepatic tissues following MDMA exposure. Recent epidemiological studies revealed that MDMA is frequently co-abused with other substances such as alcohol ethanol , cannabis marijuana , cocaine, opioids, and amphetamines \[ 87 — 91 \]. Evidence indicates that the combination of MDMA and ethanol further increases the risk of cell and organ damage i. As described earlier in this review, MDMA alone promotes hyperthermia and tissue damage in many organs. Combination of these 2 abused substances e. Moreover, ethanol or its metabolite, acetaldehyde, enhanced MDMA-mediated long term serotonergic neurotoxicity \[ 96 \], while it increased MDMA concentration in the brain \[ \], most likely through disruption of the blood brain barrier \[ \]. For instance, alcohol-mediated inactivation of mitochondrial enzymes such as ALDH2 \[ 53 \] and its isozymes \[ 57 \], involved in cellular defense against toxic acetaldehyde, acrolein, MDAL, and other reactive carbonyl compounds, may increase sensitivity toward tissue damage by MDMA or vice versa \[ 44 , 96 — \]. We recently showed that concomitant administration of MDMA with ethanol resulted in markedly suppressed ALDH2 and ALDH1 activities with elevated blood levels of acetaldehyde the quintessentially toxic primary metabolite of ethanol and enhanced hepatotoxicity in rats \[ \]. In addition, some of these abused substances such as ethanol and cocaine may increase the activities of P enzymes that are involved in the metabolism of MDMA, causing increased production of MDMA-mediated metabolites. In fact, the majority of ethanol is being metabolized by cytosolic alcohol dehydrogenase while acetaldehyde produced from ethanol metabolism is catalyzed by mitochondrial ALDH2. However, ethanol and acetaldehyde are known to decrease the levels of various anti-oxidants such as glutathione and vitamin C, likely contributing to increased oxidative stress in the presence of reactive MDMA metabolites. All these events eventually contribute to greater tissue damage initiated by MDMA, as exemplified in Fig. Synergistic interaction between MDMA and alcohol or other abused drugs. Despite numerous reports about MDMA-mediated tissue injuries, the molecular mechanisms of its pathological effects are still poorly understood. Various metabolites of MDMA including potentially toxic quinone and thioester compounds may directly or indirectly interfere with the mitochondrial electron transport system, leading to increased leakage of ROS from the mitochondria. Oxidation of lipids likely causes accumulation of lipid peroxides such as MDAL and 4-hydroxynonenal, which are toxic to the cells \[ 81 , 82 , \]. Oxidative modifications of various proteins in many different sub-cellular organelles e. Our Cys-targeted proteomics analysis revealed that many mitochondrial proteins were oxidatively-modified in MDMA-exposed rat livers, contributing to mitochondrial dysfunction \[ Fig. The oxidized proteins in other sub-cellular organelles and extra-hepatic tissues should be also characterized to further understand the roles of specific proteins in MDMA-mediated damage in a given tissue of interest. However, this Cys-targeted proteomics analysis should be complemented by the enzymatic activity measurement of an individual target protein and immunoprecipitation followed by immunoblot analysis with S-NO-Cys, glutathione, or 3-nitro-tyrosine. Furthermore, some of the potential targets including Bcl-2 family proteins involved in apoptosis of these stress-activated protein kinases need to be experimentally demonstrated in the future. Clear understanding of the toxicity mechanisms would lead to future translational research including development of efficient therapeutic agents against MDMA-mediated organ damage or deaths. Finally, the biomedical research data should be used to educate the public including MDMA users about the potential harms of MDMA use especially in conjunction with other abused substances including alcohol. We are grateful to Drs. Timothy D. The authors do not have any conflict of interest. As a library, NLM provides access to scientific literature. Curr Pharm Biotechnol. Published in final edited form as: Curr Pharm Biotechnol. Find articles by Byoung-Joon Song. Find articles by Kwan-Hoon Moon. Find articles by Vijay V Upreti. Find articles by Natalie D Eddington. Find articles by Insong J Lee. PMC Copyright notice. The publisher's version of this article is available at Curr Pharm Biotechnol. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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