Molecular analysis of mitochondrial Complex I in the levodopa short duration response in Parkinson’s Disease

ABSTRACT Introduction Significant advances have been made in elucidating the pathophysiological mechanisms of Parkinson's disease (PD). Levodopa remains the main therapeutic option — although it presents heterogeneous clinical benefits among patients. Mutations related to levodopa metabolic pathways have been investigated, but not for mtDNA. Since levodopa metabolism is highly dependent on ionic gradients, endocytosis, and vesicular transport — all ATP-dependent processes — the normal function of OXPHOS is essential not only for adequate levodopa metabolism but also for its therapeutic efficacy. This study aimed to analyze levodopa short duration responsiveness profiles considering the mitochondrial genomic component in Brazilian admixed populations. Methods A total of 49 patients with PD underwent a levodopa challenge test (LCT), followed by whole mitochondrial genome sequencing, pathogenicity prediction of identified variants, and in silico structural analyses. Results Variants most frequently affected ND4, ND5, and ND6 subunits in both groups (responsive and non-responsive). Among them, the responsive group presented variants in MT-ND4 (m.12018C>G - T420S) and ND5 (m.13130C>A - P265H) as those with the most significant structural impact, suggesting a loss of the native conformation and alterations in protein efficiency. Additionally, five unique variants were detected only among non-responsive patients, two of which were absent from the dbSNP and ClinVar databases, which indicates the possibility that they are novel variants and potentially population-specific. Conclusion We provide molecular evidence suggesting that variants in mitochondrial ND4, ND5, and ND6 subunits, in addition to mitochondrial ancestry, may contribute to distinct levodopa short duration response in PD patients.