Polyalanine tracts directly induce the release of cytochrome c, independently of the mitochondrial permeability transition pore, leading to apoptosis.
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.
Toriumi
Kazuya
K
Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Oma
Yoko
Y
Mimoto
Ai
A
Futai
Eugene
E
Sasagawa
Noboru
N
Turk
Boris
B
Ishiura
Shoichi
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010455:Peptides; C019529:polyalanine; D045304:Cytochromes c; D053148:Caspase 3