Disruption of mitochondrial complex I induces progressive parkinsonism

Patricia González-Rodríguez, Enrico Zampese, Kristen A. Stout, Jaime N. Guzman, Ema Ilijic, Ben Yang, Tatiana Tkatch, Mihaela A. Stavarache, David L. Wokosin, Lin Gao, Michael G. Kaplitt, José López-Barneo, Paul T. Schumacker and D. James Surmeier ()
Additional contact information
Patricia González-Rodríguez: Northwestern University
Enrico Zampese: Northwestern University
Kristen A. Stout: Northwestern University
Jaime N. Guzman: Northwestern University
Ema Ilijic: Northwestern University
Ben Yang: Northwestern University
Tatiana Tkatch: Northwestern University
Mihaela A. Stavarache: Weill Cornell Medical College
David L. Wokosin: Northwestern University
Lin Gao: Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla and CIBERNED
Michael G. Kaplitt: Weill Cornell Medical College
José López-Barneo: Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla and CIBERNED
Paul T. Schumacker: Northwestern University
D. James Surmeier: Northwestern University

Nature, 2021, vol. 599, issue 7886, 650-656

Abstract: Abstract Loss 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.

Date: 2021
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DOI: 10.1038/s41586-021-04059-0

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