Journal
ACS CHEMICAL NEUROSCIENCE
Volume 9, Issue 11, Pages 2849-2858Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00276
Keywords
ATP synthase; dopamine; dopamine-derived quinones; mitochondria; Parkinson's disease; permeability transition pore
Funding
- Italian Ministry of Education, University and Research [PRIN 2015T778JW]
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The preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta is responsible for the motor impairment associated with Parkinson's disease. Dopamine is a highly reactive molecule, which is usually stored inside synaptic vesicles where it is stabilized by the ambient low pH. However, free cytosolic dopamine can auto-oxidize, generating reactive oxygen species, and lead to the formation of toxic quinones. In the present work, we have analyzed the mechanisms through which the dysfunction of dopamine homeostasis could induce cell toxicity, by focusing in particular on the damage induced by dopamine oxidation products at the mitochondrial level. Our results indicate that dopamine derivatives affect mitochondrial morphology and induce mitochondrial membrane depolarization, leading to a reduction of ATP synthesis. Moreover, our results suggest that opening of the mitochondrial transition pore induced by dopamine-derived quinones may contribute to the specific Parkinson's disease-associated vulnerability of dopamine containing neurons.
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