Scheme summarizing the main findings reported in this study.

<p>The glial metabolite of MPTP, MPP+, enters into dopaminergic neurons in the SN and accumulates in the mitochondria. where it specifically binds to and inhibits complex I of the ETC. This leads to mitochondrial respiration failure, reducing ETC-OXPHOS coupling as well as the efficiency of the oxidative phosphorylation. MPP+ also promotes an increase in the production of NO^● by activation of the inducible isoform iNOS, whereas nNOS activity remains unchanged. Depletion of either iNOS or nNOS did not prevent the decrease in oxygen consumption, suggesting that MPTP-induced respiratory defects and consequent ROS production run independently of iNOS activation. The interplay of these two MPTP-dependent consequences, respiration failure and NO^● production, could generate a positive feedback loop where inflammation and oxidative damage are prevalent and cause neurodegeneration. This misbalance generates an excess of ROS by electron leak that, in combination with RNS, is known to induce the expression of inflammatory cytokines and membrane oxidative damage. Melatonin that also accumulates in the mitochondria, harnesses the activity of the respiratory complexes including the inhibition of complex I induced by MPTP as a first action. Melatonin administration restored the coupling between the ETC and OXPHOS, rescued mitochondrial respiration and reduced ROS production, by reducing electron leak and directly scavenging free radicals. On the other hand, the indoleamine also inhibits iNOS activation, reducing NO^● production and consequently reducing inflammation that closes the cycle.