Title: Neuromelanin formation exacerbates HAA-induced mitochondrial toxicity and mitophagy impairments.

Authors: Lawana, Vivek; Um, Se Young; Foguth, Rachel M; Cannon, Jason R

Published In Neurotoxicology, (2020 12)

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is a major public health concern due in part to prevalence, debilitating symptoms, and links to environmental exposures. Much research has focused on environmental factors that may lead to dopaminergic neurotoxicity that occurs in PD. In the study of neuronal uptake and neurotoxicity, critical species differences have been observed. For example, neuromelanin is a molecule formed in part by the breakdown products of dopamine metabolism, along with lipid and protein components. Interestingly, human catecholaminergic neurons contain readily detectable amounts of neuromelanin, while rodent models form far lower levels of neuromelanin that is barely detectable. This discrepancy is potentially an important translational weakness. Recently, we showed that neuromelanin formation modulates heterocyclic aromatic amine (HAA)-induced neurotoxicity in cellular models. HAAs are dietary toxins that have primarily been studied as carcinogens, with emergent literature on selective neurotoxicity. The goal of the present study was to identify whether mitochondria in neuromelanin forming cells may be especially sensitive to HAAs. Here, we exposed galactose-supplemented SH-SY5Y cells to HAAs and tested mitochondrial function and mitophagy. The ectopic formation of neuromelanin was found to increase mitochondrial oxidative stress, decrease membrane potential, increase mitochondrial bioenergetic impairments, and impair mitophagy relative to HAA-treated cells that do not form neuromelanin. These results suggest that neuromelanin has a critical role in HAA toxicity and adverse effects on mitochondria. The data also further cement the need to conduct both mechanistic and risk assessment studies on PD-relevant neurotoxicity in models that form neuromelanin.

PubMed ID: 33058929

MeSH Terms: Cell Line, Tumor; Energy Metabolism/drug effects; Harmine/analogs & derivatives*; Harmine/toxicity; Humans; Imidazoles/toxicity*; Melanins/metabolism*; Membrane Potential, Mitochondrial/drug effects; Mitochondria/drug effects*; Mitochondria/metabolism; Mitochondria/ultrastructure; Mitophagy/drug effects*; Neurons/drug effects*; Neurons/metabolism; Neurons/ultrastructure; Oxidative Stress/drug effects; Parkinsonian Disorders/chemically induced*; Parkinsonian Disorders/metabolism; Parkinsonian Disorders/pathology