Expression of polyalanine stretches induces mitochondrial dysfunction

Toriumi, Kazuya; Oma, Yoko; Kino, Yoshihiro; Futai, Eugene; Sasagawa, Noboru; Ishiura, Shoichi

doi:10.1002/jnr.21619

Cited by 22 publications

(22 citation statements)

References 51 publications

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“…In a previous study, we detected polyalanine tracts in a mitochondrial fraction, suggesting that polyalanine tracts associate with mitochondria (Toriumi et al . 2008).…”

Section: Resultsmentioning

confidence: 65%

“…In a previous study (Toriumi et al . 2008), we examined the effect of expanded polyalanine tracts fused with yellow fluorescent protein (YFP) on cultured cell lines.…”

Section: Introductionmentioning

confidence: 86%

“…In a previous study (Toriumi et al 2008), we examined the effect of expanded polyalanine tracts fused with yellow fluorescent protein (YFP) on cultured cell lines. Cells expressing the YFP-fused expanded polyalanine tracts exhibited cytotoxicity and aggregate formation like that seen in polyalanine diseases.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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In recent years, several novel types of disorder caused by the expansion of triplet repeats in specific genes have been characterized; in the "polyalanine diseases", these expanded repeats result in proteins with aberrantly elongated polyalanine tracts. In this study, we fused expanded polyalanine tracts to yellow fluorescent protein to examine their physical interaction with mitochondria. Tracts containing more than 23 alanine repeats were found to physically associate with mitochondria, strongly suggesting that an interaction between polyalanine tracts and mitochondria is a contributing factor in the pathology of polyalanine diseases. Furthermore, in in vitro experiments, polyalanine tracts induced release of cytochrome c from mitochondria and caspase-3 activation, independently of the mitochondrial permeability transition pore. These results suggest that oligomerized polyalanine tracts might induce the rupture of the mitochondrial membrane, the subsequent release of cytochrome c, and apoptosis. This novel mechanism for polyalanine tract cytotoxicity might be common to the pathogenesis of all polyalanine diseases. Further investigation of this mechanism might aid the development of therapies for these diseases.

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“…In a previous study, we detected polyalanine tracts in a mitochondrial fraction, suggesting that polyalanine tracts associate with mitochondria (Toriumi et al . 2008).…”

Section: Resultsmentioning

confidence: 65%

“…In a previous study (Toriumi et al . 2008), we examined the effect of expanded polyalanine tracts fused with yellow fluorescent protein (YFP) on cultured cell lines.…”

Section: Introductionmentioning

confidence: 86%

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

et al. 2009

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“…Collectively, these data suggest that the onset of polyglutamine and polyalanine diseases may relate to the oligomerization status of the disease‐causing protein and that oligomerization itself is facilitated by the homopolymeric sequences. We previously found that polyalanine tracts were associated with mitochondria (Toriumi et al, 2008). Chaperone proteins such as Hsp40 and Hsp70 were also colocalized with aggregates formed by mutant PABPN1 having polyalanine expansion (Wang et al, 2005).…”

Section: Discussionmentioning

confidence: 94%

Biochemical analysis of oligomerization of expanded polyalanine repeat proteins

Nojima

Oma

Futai

et al. 2009

J of Neuroscience Research

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Many human proteins contain amino acid repeats that can form homopolymeric amino acid (HPAA) tracts. HPAA tract proteins that contain polyalanine sequences promote diseases, including oculopharyngeal muscular dystrophy. The pathological properties of these proteins develop when the repeats match or exceed approximately 20 residues. We analyzed the oligomerization of yellow fluorescent protein (YFP) and GST fusion proteins containing >20 alanine repeats by using sucrose density gradient centrifugation. YFP and GST fusion proteins having 23 polyalanine residues sedimented readily in sucrose density gradients, suggesting instability and oligomerization of proteins with an excess of 20 alanine repeats. Moreover, GST fusion proteins were resistant to trypsin digestion after oligomerization. Oligomerized artificial proteins with long polyalanine repeats may be suitable models for studying polyalanine-related diseases.

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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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Expression of polyalanine stretches induces mitochondrial dysfunction

Cited by 22 publications

References 51 publications

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

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

Biochemical analysis of oligomerization of expanded polyalanine repeat proteins

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

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