Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction

Oliveira, Paulo J.; Wallace, Kendall B.

doi:10.1016/j.tox.2005.12.009

Cited by 88 publications

(61 citation statements)

References 36 publications

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“…state 3 respiration rate, sustained by Complex Ilinked substrates for the analysis of Complex I, III and IV. For the ANT, a protocol similar to what was previously established in our group was used (Oliveira and Wallace, 2006). Table S3 shows the maximal state 3 respiration rates for each tissue and treatment group and were found to be consistently lower in cardiac mitochondria from DOX-treated rats, as previously reported (Pereira et al, 2012).…”

Section: Global Step -Titration Curves Of Oxygen Consumptionmentioning

confidence: 69%

“…Our starting hypothesis was based on DOX effects on respiratory complexes and mitochondrial carriers (Cheneval et al, 1983;Davies and Doroshow, 1986;Nicolay and de Kruijff, 1987;Oliveira and Wallace, 2006;Yao et al, 2011). We had anticipated that OXPHOS enzymatic reserves were lower in the heart or, alternatively, that OXPHOS in heart mitochondria was dependent in one particular respiratory complex, more so than liver or kidney.…”

Section: Discussionmentioning

confidence: 99%

“…This futile cycle is considered to be one of the major ROS production sites in DOX-induced toxicity (Davies and Doroshow, 1986). Additionally, DOX has been reported to interfere with Complex III and IV (Nicolay and de Kruijff, 1987), the phosphate carrier (Cheneval et al, 1983) and the adenine nucleotide translocator (ANT) (Oliveira and Wallace, 2006), among other mitochondrial proteins. Although most of the studies report effects in heart or cardiac-like models, some of DOX effects are shared among other tissues (Nicolay and de Kruijff, 1987;Santos et al, 2002;Yao et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

Pereira

Tavares

et al. 2016

Mitochondrion

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Aims: It is still unclear why anthracycline treatment results in a cardiac-specific myopathy. We investigated whether selective doxorubicin (DOX) cardiotoxicity involving mitochondrial degeneration is explained by different respiratory complexes reserves between tissues by comparing and contrasting treatment effects in heart vs liver and kidney. Alternatively, we have also explored if the degeneration is due to alterations of mitochondrial thresholds to incompatible states. Methods and results: Heart, liver and kidney mitochondria were isolated from male Wistar rats weekly injected with DOX during 7 weeks. Global flux and isolated step curves were obtained for Complex I, III, IV, as well as for the adenine nucleotide translocator. We show treatment-related alterations in global flux curve for Complex III in all analyzed tissues and in Complex IV activity curve solely in heart. However, all mitochondrial threshold curves remained unchanged after treatment in the analyzed tissues. No treatment-related differences were detected on transcript or protein analysis of selected respiratory complexes subunits. However, a specific loss of cytochrome c and cardiolipin was measured in heart, but not in other organs, mitochondria from DOX-treated animals. Conclusions: Contrary to our hypothesis, impaired mitochondrial respiration could not be explained by intrinsic differences in respiratory complexes reserves among tissues or, by alterations in mitochondrial thresholds after treatment. Instead, we propose that loss of cytochrome c and cardiolipin are responsible for the depressed mitochondrial respiration observed after chronic DOX treatment. Moreover, cardiac cytochrome c and cardiolipin depletion decreases metabolic network buffering, hindering cardiac ability to respond to increased workload, accelerating cardiac aging.

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Section: Global Step -Titration Curves Of Oxygen Consumptionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

Pereira

Tavares

et al. 2016

Mitochondrion

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“…Numerous studies have been performed to understand why Dox is selectively cardiotoxic. In vivo models of Dox-induced cardiomyopathy (Oliveira and Wallace 2006;Santos et al 2002) and in Fig. 6 Alteration of nuclear lamina induced by doxorubicin treatment.…”

Section: Discussionmentioning

confidence: 99%

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

et al. 2008

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Doxorubicin (Dox) is a very potent antineoplastic agent used against several types of cancer, despite a cumulative cardiomyopathy that reduces the therapeutic index for treatment. H9c2 myoblast cells have been used as an in vitro model to study biochemical alterations induced by Dox treatment on cardiomyocyte cells. Despite the extensive work already published, few data are available regarding morphological alterations of H9c2 cells during Dox treatment. The purpose of the present work was to evaluate Doxinduced morphological alterations in H9c2 myoblasts, focusing especially on the nuclei, mitochondria, and structural fibrous proteins. Treatment of H9c2 cell with low concentrations of Dox causes alterations in fibrous structural proteins including the nuclear lamina and sarcomeric cardiac myosin, as well as mitochondrial depolarization and fragmentation, membrane blebbing with cell shape changes, and phosphatidylserine externalization. For higher Dox concentrations, more profound alterations are evident, including nuclear swelling with disruption of nuclear membrane structure, mitochondrial swelling, and extensive cytoplasm vacuolization. The results obtained indicate that Dox causes morphological alterations in mitochondrial, nuclear, and fibrous protein structures in H9c2 cells, which are dependent on the drug concentration. Data obtained with the present study allow for a better characterization of the effects of Dox on H9c2 myoblasts, used as a model to study Dox-induced cardiotoxicity. The results obtained also provide new and previously unknown targets that can contribute to understand the mechanisms involved in the cardiotoxicity of Dox.

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“…Recent studies identified the ANT as one important target for ROS induced by anticancer drugs, such as doxorubicin and arsenic trioxide. In particular, it was demonstrated that doxorubicin-induced cardiac toxicity correlates with oxidation of SH-groups in ANT and a decrease in ANT protein concentration, with inhibition of mitochondrial respiration and increased probability of MPT pore formation as consequences thereof [35] (Fig. 3).…”

Section: Damage To Lipidsmentioning

confidence: 99%

Mitochondria, oxidative stress and cell death

et al. 2007

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In addition to the well-established role of the mitochondria in energy metabolism, regulation of cell death has recently emerged as a second major function of these organelles. This, in turn, seems to be intimately linked to their role as the major intracellular source of reactive oxygen species (ROS), which are mainly generated at Complex I and III of the respiratory chain. Excessive ROS production can lead to oxidation of macromolecules and has been implicated in mtDNA mutations, ageing, and cell death. Mitochondriagenerated ROS play an important role in the release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and apoptosis. Cytochrome c release occurs by a two-step process that is initiated by the dissociation of the hemoprotein from its binding to cardiolipin, which anchors it to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and results in an increased level of "free" cytochrome c in the intermembrane space. Conversely, mitochondrial antioxidant enzymes protect from apoptosis. Hence, there is accumulating evidence supporting a direct link between mitochondria, oxidative stress and cell death.

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Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats—Relevance for mitochondrial dysfunction

Cited by 88 publications

References 36 publications

Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

Mitochondria, oxidative stress and cell death

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