Fig. 1.

Mechanism of action of neurotoxins inducing PD. MPTP readily crosses the blood-brain barrier and is taken up by nearby astroglia which subsequently convert it to MPP⁺ via MAO-B. Extracellularly released MPP⁺ is then actively taken up via DAT and accumulates within mitochondria of DA neurons where it inhibits mitochondrial CI of the ETC resulting in ROS production and energetic deficiency. Similarly, the pesticide rotenone (Rot), due to its high lipophilicity, readily crosses biological membranes and reaches the inner mitochondrial membrane where it inhibits CI. In contrast, paraquat (PQ²⁺) relies on the LAT1 to cross the blood-brain barrier. Hereafter, it is taken up by DAT or OCT3 into DA neurons and generates ROS by redox cycling at CI and CIII of the ETC. Abbreviations: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 1-methyl-4-phenylpyridinium (MPP⁺); coenzyme Q (CoQ); dopamine (DA); dopamine transporter (DAT); L-amino acid transporter (LAT1); mitochondrial Complex I (CI); mitochondrial Complex II (CII); mitochondrial Complex III (CIII); mitochondrial Complex IV (CIV); mitochondrial Complex V (CV); monoamino oxidase B (MAO-B); organic cation transporter 3 (OCT3); paraquat (PQ²⁺); reactive oxygen species (ROS); rotenone (Rot); vesicular monoamino transporter (VMAT). Created with BioRender.com