Distinct Mitochondrial States Modulate α-Synuclein Toxicity

Abnormal α-synuclein (α-syn) accumulation and mitochondrial dysfunction are central features of Parkinson's disease (PD), and increasing evidence suggests that these processes are closely connected. Using yeast models to manipulate mitochondrial metabolic states, we investigated how mitochondrial activity may affect α-syn accumulation and toxicity. Under the fermentative growth condition, we found that α-syn localized predominantly to the plasma membrane and was non-toxic. Respiratory growth induced cytoplasmic α-syn accumulation, mitochondrial abnormalities, and marked toxicity dependent on α-syn expression and membrane binding. Surprisingly, genetic disruption of mitochondrial respiration also enhanced α-syn toxicity despite causing little α-syn accumulation, indicating that both increased demand of mitochondrial respiratory function and compromised respiratory capacity can sensitize cells to α-syn toxicity. Overexpression of HAP4 , a master regulator of mitochondrial biogenesis and respiratory gene expression, suppressed α-syn toxicity, but this protection required functional mitochondria. Together, these findings demonstrate that distinct mitochondrial functional states exert markedly different effects on α-syn toxicity and reveal a complex relationship between mitochondrial function and cellular response to α-syn expression. These models provide a new system for investigating how changes in mitochondrial function contribute to α-syn-induced cellular stress.