Neuromelanin formation exacerbates HAA-induced mitochondrial toxicity and mitophagy impairments.
Neuromelanin formation exacerbates HAA-induced mitochondrial toxicity and mitophagy impairments.
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DOI：
10.1016/j.neuro.2020.10.005
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发表时间：
2020-12
期刊：
影响因子：
3.4
通讯作者：
Cannon JR
中科院分区：
文献类型：
--
作者：
Lawana V;Um SY;Foguth RM;Cannon JR
帕金森病（PD）是一种进行性神经退行性疾病，部分由于患病率、衰弱症状以及与环境暴露的联系，它是一个主要的公共卫生问题。许多研究都集中在环境因素，可能会导致多巴胺能神经毒性发生在PD。在神经元摄取和神经毒性的研究中，观察到了关键的种属差异。例如，神经黑色素是一种分子，部分由多巴胺代谢的分解产物形成，沿着脂质和蛋白质成分。有趣的是，人类的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，我们发现，神经黑色素形成调节杂环芳香胺（HAA）诱导的神经毒性的细胞模型。哈斯是膳食毒素，主要被研究为致癌物，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对哈斯特别敏感。在这里，我们将补充半乳糖的SH-SY 5 Y细胞暴露于哈斯，并测试线粒体功能和线粒体自噬。神经黑色素的异位形成被发现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，并损害相对于不形成神经黑色素的经HAA处理的细胞的线粒体自噬。这些结果表明，神经黑色素在HAA毒性和对线粒体的不良影响中具有关键作用。这些数据还进一步证实了在形成神经黑色素的模型中对PD相关神经毒性进行机制和风险评估研究的必要性。
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.
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影响因子：
3.6
作者：
Kanthasamy AG;Kitazawa M;Yang Y;Anantharam V;Kanthasamy A
通讯作者：
Kanthasamy A
影响因子：
3.8
作者：
Griggs, Amy M.;Agim, Zeynep S.;Cannon, Jason R.
通讯作者：
Cannon, Jason R.
影响因子：
4.6
作者：
Charkoudian, LK;Franz, KJ
通讯作者：
Franz, KJ
DOI：
10.1073/pnas.87.23.9368
发表时间：
1990-12-01
影响因子：
11.1
作者：
ALBORES, R;NEAFSEY, EJ;COLLINS, MA
通讯作者：
COLLINS, MA
影响因子：
13.3
作者：
Dagda, Ruben K.;Zhu, Jianhui;Chu, Charleen T.
通讯作者：
Chu, Charleen T.