Polyalanine tracts directly induce the release of cytochrome <i>c</i>, independently of the mitochondrial permeability transition pore, leading to apoptosis

Toriumi, Kazuya; Oma, Yoko; Mimoto, Ai; Futai, Eugene; Sasagawa, Noboru; Turk, Boris; Ishiura, Shoichi

doi:10.1111/j.1365-2443.2009.01307.x

Cited by 8 publications

(8 citation statements)

References 21 publications

(40 reference statements)

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“…Respiratory chain enzymes are also susceptible to free radical-induced oxidative damage (60), therefore an increased oxidative stress may also contribute to the decreased complex I activity, as suggested in the transcriptomic analysis (response to oxidative stress, GO:0006979). Toriumi et al (61) have recently shown that the polyalanine tract may induce mitochondrial dysfunction with the rupture of the mitochondrial membrane, release of cytochrome c and apoptosis (62). We demonstrated here that the reduction in muscle force was not just a consequence of muscle atrophy-as observed with the reduced specific force-so expPABPN1 expression clearly has a deleterious effect in force production potentially via mitochondrial dysfunction or oxidative stress, which will both need to be studied in more detail.…”

Section: Discussionsupporting

confidence: 50%

Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

Trollet

Anvar

Venema

et al. 2010

Human Molecular Genetics

127

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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)(8-13) expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.

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Section: Discussionsupporting

confidence: 50%

Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

Trollet

Anvar

Venema

et al. 2010

Human Molecular Genetics

127

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“…Our results showed that in the UACC-62 cells, NACC induced Cyto c release via MOMP by upregulated Bax and was not PTP-dependent. The results were consistent with a previous report which found that the regulatory release of Cyto c from mitochondria could occur independently through regulation of PTP opening (47).…”

Section: Discussionsupporting

confidence: 93%

N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine induces mitochondrial-mediated apoptosis and suppresses migration in melanoma cells

Chen

Jiang

Zhang³

et al. 2015

Oncology Reports

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We previously reported that N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC) induces apoptosis in human melanoma UACC-62 cells. In the present study, the molecular mechanism of NACC‑induced apoptosis in melanoma cells was investigated. Briefly, the apoptosis triggered by NACC was confirmed in UACC‑62 cells for shorter treatment periods. Increased activities of caspase‑3 and caspase‑9 but not caspase‑8 were observed in the cell lysates. Western blotting showed that the pro‑apoptotic protein Bax was upregulated and the anti‑apoptotic protein Mcl‑1 was downregulated and cytochrome c (Cyto c) was released into the cytosol. Flow cytometric analysis demonstrated that NACC induced significant mitochondrial membrane potential disruption. Significant increases in the generation of reactive oxygen species (ROS) and cytosolic calcium elevation were also observed. However, opening of the mitochondrial permeability transition pore which could be involved in Cyto c leakage from mitochondria was found to be unaffected by NACC. Taken together, all the results presented in this study including apoptotic induction, activation of the caspase‑3 and ‑9 cascade, upregulation of Bax, downregulation of Mcl‑1, Cyto c release from the mitochondria, mitochondrial membrane potential depletion, ROS production and cytosolic calcium elevation demonstrated that NACC triggered apoptosis in the UACC‑62 cells via the mitochondrial‑dependent pathway. Melanoma is well‑known as an aggressive and highly metastatic disease. In this study, we also investigated the effects of NACC on the migration of UACC‑62 cells using the xCELLigence system. The results revealed that in vitro NACC is capable of inhibiting the migration of melanoma cells.

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“…However, mitochondrial dysfunction, the formation of the mitochondrial permeability transition pore, Cyt. c release, and the translocation of pro-apoptotic BAX to mitochondria have been observed in mammalian polyA models (Toriumi et al, 2008, 2009; Bhattacharjee et al, 2012). Therefore, it might be a fruitful approach to dissect the role of mitochondria in polyA-triggered cytotoxicity in yeast.…”

Section: Neurotoxic Yeast Modelsmentioning

confidence: 98%

Mitochondrion-mediated cell death: dissecting yeast apoptosis for a better understanding of neurodegeneration

Braun¹

2012

Front. Oncol.

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Mitochondrial damage and dysfunction are common hallmarks for neurodegenerative disorders, including Alzheimer, Parkinson, Huntington diseases, and the motor neuron disorder amyotrophic lateral sclerosis. Damaged mitochondria pivotally contribute to neurotoxicity and neuronal cell death in these disorders, e.g., due to their inability to provide the high energy requirements for neurons, their generation of reactive oxygen species (ROS), and their induction of mitochondrion-mediated cell death pathways. Therefore, in-depth analyses of the underlying molecular pathways, including cellular mechanisms controlling the maintenance of mitochondrial function, is a prerequisite for a better understanding of neurodegenerative disorders. The yeast Saccharomyces cerevisiae is an established model for deciphering mitochondrial quality control mechanisms and the distinct mitochondrial roles during apoptosis and programmed cell death. Cell death upon expression of various human neurotoxic proteins has been characterized in yeast, revealing neurotoxic protein-specific differences. This review summarizes how mitochondria are affected in these neurotoxic yeast models, and how they are involved in the execution and prevention of cell death. I will discuss to which extent this mimics the situation in other neurotoxic model systems, and how this may contribute to a better understanding of the mitochondrial roles in the human disorders.

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Polyalanine tracts directly induce the release of cytochrome c, independently of the mitochondrial permeability transition pore, leading to apoptosis

Cited by 8 publications

References 21 publications

Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine induces mitochondrial-mediated apoptosis and suppresses migration in melanoma cells

Mitochondrion-mediated cell death: dissecting yeast apoptosis for a better understanding of neurodegeneration

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