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Toxin-Mediated Complex I Inhibition and Parkinson’s Disease

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Mitochondrial Mechanisms of Degeneration and Repair in Parkinson's Disease

Abstract

Evidence of decreased mitochondrial complex I activity within the brain and peripheral tissues of idiopathic and familial forms of Parkinson’s disease (PD) implies an intrinsic vulnerability in the first complex of the electron transport chain (ETC). Several toxins of synthetic and natural origin have the ability to specifically inhibit complex I and reproduce parkinsonian-like features with remarkable similarity. Central to this mechanism is the selective vulnerability of the dopaminergic neurons of the substantia nigra (SN) and their axonal projections to the striatum (ST) to complex I inhibition. While no single etiological factor has been identified as the cause for the degeneration of dopamine neurons in sporadic PD, several lines of evidence suggest that loss of complex I activity is intimately related to the hallmark pathological features of the disease, including elevated levels of oxidative stress, neuroinflammation, and protein aggregation. The function of complex I and its production of reactive oxygen species following dysregulation are highlighted here, as well as the resulting neuropathology and its specific implications for the dopaminergic system.

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Authors and Affiliations

  1. Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Briana R. De Miranda Ph.D. & Laurie H. Sanders Ph.D.

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Bennett Van Houten Ph.D.

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  1. College of Health Sciences, Midwestern University, Glendale, Arizona, USA

    Lori M. Buhlman

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De Miranda, B.R., Van Houten, B., Sanders, L.H. (2016). Toxin-Mediated Complex I Inhibition and Parkinson’s Disease. In: Buhlman, L. (eds) Mitochondrial Mechanisms of Degeneration and Repair in Parkinson's Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-42139-1_6

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