Functional Mitochondria Are Required for α-Synuclein Toxicity in Aging Yeast

α-Synuclein is one of the principal toxic triggers of Parkinson disease, an age-associated neurodegeneration. Using old yeast as a model of α-synuclein expression in post-mitotic cells, we show that α-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 α-synuclein-induced cell killing. However, abrogation of mitochondrial DNA (rho 0 ) inhibited α-synuclein-induced reactive oxygen species formation and subsequent apoptotic cell death. Thus, introducing an aging yeast model of α-synuclein toxicity, we demonstrate a strict requirement of functional mitochondria.