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.

帕金森病 (PD) 是一种进行性神经退行性疾病，是一个主要的公共卫生问题，部分原因是患病率、使人衰弱的症状以及与环境暴露的联系。许多研究都集中在可能导致 PD 中发生的多巴胺能神经毒性的环境因素上。在神经元摄取和神经毒性的研究中，观察到了关键的物种差异。例如，神经黑色素是一种部分由多巴胺代谢的分解产物以及脂质和蛋白质成分形成的分子。有趣的是，人类儿茶酚胺能神经元含有容易检测到的神经黑色素，而啮齿动物模型形成的神经黑色素水平要低得多，几乎检测不到。这种差异可能是一个重要的翻译弱点。最近，我们表明，神经黑色素的形成可调节杂环芳胺 (HAA) 诱导的细胞模型中的神经毒性。HAA 是膳食毒素，主要作为致癌物进行研究，并有关于选择性神经毒性的新兴文献。本研究的目的是确定神经黑色素形成细胞中的线粒体是否可能对 HAA 特别敏感。在这里，我们将补充半乳糖的 SH-SY5Y 细胞暴露于 HAA，并测试了线粒体功能和线粒体自噬。与未形成神经黑色素的 HAA 处理的细胞相比，神经黑色素的异位形成被发现会增加线粒体氧化应激，降低膜电位，增加线粒体生物能量损伤，并损害线粒体自噬。这些结果表明神经黑色素在 HAA 毒性和对线粒体的不利影响中具有关键作用。