Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson’s disease#

Authors#

Chiara Buoso, Markus Seifert, Martin Lang, Corey Griffith, Begoña Talavera Andújar, Maria Paulina Castelo, Christine Fischer, Carolina Doerrier, Heribert Talasz, Alessandra Zanon, Peter P. Pramstaller, Emma Schymanski, Irene Pichler, Guenter Weiss

Abstract#

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the degeneration of dopaminergic neurons in Parkinson’s disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and PD patient with mutations in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in regulation of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to impaired mitochondrial respiration and related mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired iron-dependent aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. Of note, the hiPSC-derived PD neurons harboring an endogenous SNCA mutation presented with altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and subtle alterations of tricarboxylic acid cycle linked metabolic pathways as compared to control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by improving mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels involved in mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in neuronal cells. The disturbed regulatory network in PD cells can be restored by supplementation of dopamine.