Gonzalez-Rodriguez, PatriciaZampese, EnricoStout, Kristen AGuzman, Jaime NIlijic, EmaYang, BenTkatch, TatianaStavarache, Mihaela AWokosin, David LGao, LinKaplitt, Michael GLopez-Barneo, JoseSchumacker, Paul TSurmeier, D James2025-01-072025-01-072021-11-03González-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature. 2021 Nov;599(7886):650-656.https://hdl.handle.net/10668/27577Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.enAnimalsDendritesDopamineFemaleMiceParkinsonian DisordersSubstantia NigraAxonsCell DeathDisease Models, AnimalDisease ProgressionDopaminergic NeuronsElectron Transport Complex ILevodopaMaleMotor SkillsNADH DehydrogenasePhenotyperesearch article34732887Restricted AccessDopaminaTrastornos ParkinsonianosEnfermedad de ParkinsonNeuronas DopaminérgicasRatonesHumanosMetabolismoGenéticaAxonesFenotipoSobrevidaAprendizajeLevodopa10.1038/s41586-021-04059-01476-4687PMC9189968https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9189968https://pmc.ncbi.nlm.nih.gov/articles/PMC9189968/pdf