Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin

Palmeira, Carlos M.; Serrano, Jose A.; Kuehl, Douglas W.; Wallace, Kendall B.

doi:10.1016/s0005-2728(97)00055-8

Cited by 95 publications

(50 citation statements)

References 36 publications

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“…Experiments with human hepatic cell lines also showed that almost half of the metal accumulates in the mitochondria where it causes ultrastructural alterations, as observed by transmission electron microscopy [40]. Most of the bioenergetic experiments with Hg report the uncoupling of oxidative phosphorylation [72], inhibition of ATP synthesis [10], impairment of the respiratory chain [58] and depletion of intracellular ATP and ADP [55]. A study using a selective probe for mitochondrial reactive oxygen intermediates as well as other probes demonstrated a significant MeHg-induced increase in intracellular superoxide anion, hydrogen peroxide and hydroxyl radicals, indicating that the mitochondrial electron transport chain is an early, primary site for ROS formation [2,65,66,74].…”

Section: Discussionmentioning

confidence: 99%

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Yin¹,

Milatović²,

Aschner³

et al. 2007

Brain Research

161

100

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The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F 2 -isoprostanes (F 2 -IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 μ M MeHg for 1 or 6 hours. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (ΔΨm), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that ΔΨ m is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 μ M. MeHg pretreatment (1, 5 and 10 μ M) for 30 min also inhibited the net uptake of glutamine ( 3 H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 μ M) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 μ M) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.Please send request for reprints to Michael Aschner, Ph.D.,

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Section: Discussionmentioning

confidence: 99%

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Yin¹,

Milatović²,

Aschner³

et al. 2007

Brain Research

161

100

View full text Add to dashboard Cite

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“…It was found that DOX had high affinity for cardiolipin, the phospholipid in the inner mitochondrial membrane [24] . This affinity results in the accumulation of DOX in cardiac myocytes with higher concentrations than that in other cells [25] , and causes oxidative damage on mitochondrial membranes, the respiratory chain, and DNA [26][27][28] . On the other hand, the mitochondrial respiratory chain is the major source of superoxide, thus, mitochondria are more susceptible to oxidative damage than the rest of the cells [29] .…”

Section: Discussionmentioning

confidence: 99%

Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Jin

Pan

et al. 2006

Acta Pharmacologica Sinica

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Aim: To investigate the effects of deferiprone on doxorubicin-induced cardiotoxicity and determine its protection on cardiac contractility in vivo at tissue level. Methods: Spontaneously-beating isolated atria from rats were pretreated with deferiprone for 10 min at 1.2 mmol/L or 0.3 mmol/L, respectively before co-incubation with doxorubicin (DOX) at 0.03 mmol/L for 60 min. Contractility (dF/dt) was assessed every 10 min during the incubation. After that, the tissues around the sinuatrial nodes were fixed for ultrastructural study; succinate dehydrogenase (SDH) and Cu, Zn superoxide dismutase (Cu, Zn-SOD) activity, as well as malondialdehyde (MDA) level of the atria were assayed. Results: Treatment with DOX alone resulted in a 49.34% reduction of the contractility, mitochondria swelling, disruption of mitochondrial crista and decreased electron density of the matrices. Conversely, with the presence of deferiprone, the negative inotropic effect and lesions in the cardiac mitochondria structure induced by DOX were attenuated. Cu, Zn-SOD activity increased by 12.97%-12.11%, the MDA level decreased by 29.12%-39.82% and succinate dehydrogenase (SDH) activity was ameliorated by 25.15%-34.76%. Conclusion : Deferiprone can efficiently preserve cardiac contractility. Moreover, the results of this study indicate that deferiprone is able to protect mitochondrial function and structure form damage induced by DOX. This cardiac protective potential of deferiprone could be due to its defense capability against oxidative damage.

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“…Numerous studies strongly support reactive species as playing a prominent role in mtDNA deletions through oxidative damage. Under conditions of oxidative stress, accumulation of signifi cantly higher levels of DNA oxidation product 8-hydroxydeoxyguanosine in mtDNA compared to nuclear DNA and increased degradation of the mutated mtDNA is shown in a variety of in vitro and in vivo conditions (Palmeira et al 1997, Williams et al 1998, Serrano et al 1999. It is postulated that increased ROS production may lead to mutations and eventually degradation of oxidatively damaged mtDNA, thus accounting for decreased assembly and activity of respiratory complexes in chagasic myocardium.…”

Section: Factors Contributing To Mitochondrial Dysfunctionmentioning

confidence: 99%

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress

Zacks

Wen

Vyatkina

et al. 2005

An. Acad. Bras. Ciênc.

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There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stressinduced injuries that may contribute to disease progression. Pathogen invasion-and replication-mediated cellular injuries and immune-mediated cytotoxic reactions are the common source of reactive oxygen species (ROS) in infectious etiologies. However, our understanding of the source and role of oxidative stress in chagasic cardiomyopathy (CCM) remains incomplete. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, electron transport chain dysfunction and its role in sustaining oxidative stress in myocardium. We discuss the literature reporting the consequences of sustained oxidative stress in CCM pathogenesis.Key words: chagasic cardiomyopathy, reactive oxygen species, inflammation, mitochondria, oxidant/antioxidant status, oxidative damage. PARASITE, VECTOR AND TRANSMISSIONTrypanosoma cruzi, a parasitic protozoan of the ancient branch of eukaryotes (Kingdom Eukaryota, Order Kinetoplastida), is the etiological agent of Chagas disease in humans (Miles 2003). Currently, the World Health Organization estimates that 11-18 million individuals are infected worldwide (WHO 2002). Transmission of T. cruzi occurs predominantly via insect vectors of the subfamily Triatoma, family Reduviidae, referred to as " kissing bugs". Residing in the peridomestic habitat of mud-thatch Correspondence to: Nisha Garg Ph.D. E-mail: nigarg@utmb.edu houses in rural areas (Mott et al. 1978), Triatoma infestans in South America, Rhodnius prolixus in Venezuela, Colombia and Central America (Schofi eld and Dias 1999), and Triatoma barberi in Mexico (Guzman 2001), are the most common species responsible for transmission. Improvements in housing conditions and vector control measures instituted by the Southern Cone Initiative in 1991 have contributed to a decline in transmission in endemic countries (Schofi eld and Dias 1999). However, concern remains that reinfestation of homes by secondary sylvatic vectors, e.g. Triatoma sordida, will compromise the long-term effi cacy of vector control measures in Brazil and other Southern American countries (Monteiro et al. 2001, WHO 2002. Blood transfusion and organ transplantation represent further routes of T. cruzi transmission. Although many countries in Latin America screen blood donations for T. cruzi, infection rates ranging from 0.1% to 24.4% are estimated to occur through transfusion (WHO 2002).In the U.S., vector-transmitted human infections have been reported in the southern States (Ochs et al. 1996, Herwaldt et al. 2000. Several studies have shown the presence of the insect vector as well as infection of domestic dogs and wild animals in the US (Meurs et al. 1998, Bradley et al. 2000, Beard et al. 2003, Yabsley and Noblet 2002. Further, due to signifi cant increases in immigration to the USA and Canada from endemic countries and perinatal transmission, it is estimated that ∼ 100, 000 people residing...

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Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin

Cited by 95 publications

References 36 publications

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

An overview of chagasic cardiomyopathy: pathogenic importance of oxidative stress

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