Mitochondrial dysfunctions are common findings in neurodegenerative diseases, particularly in Parkinson's disease(PD), where alpha-synuclein encoded by the SNCA gene has been observed to localize within the organelle as the disease progresses. Despite alpha-synuclein's significance in PD pathology, its specific roles within mitochondria still need to be better understood. In this study, we aimed to explore the impact of overexpression of the SNCA gene, which codes for the alpha-synuclein protein, on the expression of genes encoded by mitochondrial DNA (mtDNA).HEK-293T cells were transfected with SNCA-encoded overexpression plasmids.MOCK plasmid transfected cells and untreated cells were used as controls.RNA isolations were performed at 48,72 and 96 hours post-transfection. The expression of 13 respiratory complex genes, two mitochondrial rRNA genes, and three mitochondrial tRNA genes encoded by mtDNA was investigated by qRT-PCR after cDNA synthesis. Statistical analysis of the results was conducted using one-way ANOVA test with GraphPad Prism 8.At 48 h in SNCA overexpression group, expression of MTtRNA3 decreased when compared with MOCK group. At 72 h in SNCA group, expressions of MTND1,MTND4,MTND4L,MTND5,MTND6,MTCYB,MTCO1, MTCO2,MTCO3,MTRNR1,MTRNR2,MTATP6,MTATP8,MTtRNA2,MTtrNA3,D-loop increased when compared to MOCK group.At 96h in SNCA group, expressions of MTND1,MTND4,MTND4L,MTND5,MTCYB, MTCO1,MTCO3,MTRNR2,MTATP6,MTATP8,MTtRNA2,D-loop increased when compared with MOCK group.These findings have shown that alpha-synuclein may play a role in mtDNA gene expression, contributing to observed mitochondrial dysfunction in PD. Besides, this study lays the groundwork for understanding alpha-synuclein-mediated changes in mtDNA gene expression and its implications in PD pathology.This study supported by TUBİTAK (Project no: 219Z179)