Functional mitochondria are required for alpha-synuclein toxicity in aging yeast.
alpha-Synuclein is one of the principal toxic triggers of Parkinson disease, an age-associated neurodegeneration. Using old yeast as a model of alpha-synuclein expression in post-mitotic cells, we show that alpha-synuclein toxicity depends on chronological aging and results in apoptosis as well as necrosis. Neither disruption of key components of the unfolded protein response nor deletion of proapoptotic key players (including the yeast caspase YCA1, the apoptosis-inducing factor AIF1, or the serine protease OMI) did prevent alpha-synuclein-induced cell killing. However, abrogation of mitochondrial DNA (rho(0)) inhibited alpha-synuclein-induced reactive oxygen species formation and subsequent apoptotic cell death. Thus, introducing an aging yeast model of alpha-synuclein toxicity, we demonstrate a strict requirement of functional mitochondria.
Büttner
Sabrina
S
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Bitto
Alessandro
A
Ring
Julia
J
Augsten
Manuela
M
Zabrocki
Piotr
P
Eisenberg
Tobias
T
Jungwirth
Helmut
H
Hutter
Sylvia
S
Carmona-Gutierrez
Didac
D
Kroemer
Guido
G
Winderickx
Joris
J
Madeo
Frank
F
D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology*; D000074923:High-Temperature Requirement A Serine Peptidase 2; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; C443623:AIF1 protein, S cerevisiae; D009247:NADH, NADPH Oxidoreductases; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases; C456272:MCA1 protein, S cerevisiae