Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
Chem Res Toxicol. 2024 Jul 15;37(7):1139-1154. doi: 10.1021/acs.chemrestox.4c00066. Epub 2024 Jun 14.
Mitochondrial dysfunction is often linked to neurotoxicity and neurological diseases and stems from oxidative stress, yet effective therapies are lacking. Deoxynivalenol (DON or vomitoxin) is one of the most common and hazardous type-B trichothecene mycotoxins, which contaminates crops used for food and animal feed. Despite the abundance of preliminary reports, comprehensive investigations are scarce to explore the relationship between these fungal metabolites and neurodegenerative disorders. The present study aimed to elucidate the precise role of DON in mitochondrial dynamics and cell death in neuronal cells. Excessive mitochondrial fission is associated with the pathology of several neurodegenerative diseases. Human SH-SY5Y cells were treated with different concentrations of DON (250-1000 ng/mL). Post 24 and 48 h DON treatment, the indexes were measured as follows: generation of reactive oxygen species (ROS), ATP levels, mitochondrial membrane potential, calcium levels, and cytotoxicity in SH-SY5Y cells. The results showed that cytotoxicity, intracellular calcium levels, and ROS in the DON-treated group increased, while the ATP levels and mitochondrial membrane potential decreased in a dose-dependent manner. With increasing DON concentrations, the expression levels of P-Drp-1, mitochondrial fission proteins Mff, and Fis-1 were elevated with reduced activities of MFN1, MFN2, and OPA1, further resulting in an increased expression of autophagic marker LC3 and beclin-1. The reciprocal relationship between mitochondrial damage and ROS generation is evident as ROS can instigate structural and functional deficiencies within the mitochondria. Consequently, the impaired mitochondria facilitate the release of ROS, thereby intensifying the cycle of damage and exacerbating the overall process. Using specific hydroxyl, superoxide inhibitors, and calcium chelators, our study confirmed that ROS and Ca2+-mediated signaling pathways played essential roles in DON-induced Drp1 phosphorylation. Therefore, ROS and mitochondrial fission inhibitors could provide critical research tools for drug development in mycotoxin-induced neurodegenerative diseases.
线粒体功能障碍通常与神经毒性和神经疾病有关，其根源在于氧化应激，但目前缺乏有效的治疗方法。脱氧雪腐镰刀菌烯醇（DON 或呕吐毒素）是最常见和最危险的 B 型单端孢霉烯族毒素之一，它污染了用于食品和动物饲料的农作物。尽管有大量的初步报告，但缺乏全面的调查来探讨这些真菌代谢物与神经退行性疾病之间的关系。本研究旨在阐明 DON 在神经元细胞中线粒体动力学和细胞死亡中的精确作用。过度的线粒体裂变与几种神经退行性疾病的病理学有关。用人 SH-SY5Y 细胞用不同浓度的 DON（250-1000ng/ml）处理。DON 处理 24 和 48 小时后，测量以下指标：活性氧（ROS）的产生、ATP 水平、线粒体膜电位、钙水平和 SH-SY5Y 细胞的细胞毒性。结果表明，DON 处理组细胞毒性、细胞内钙水平和 ROS 增加，而 ATP 水平和线粒体膜电位呈剂量依赖性下降。随着 DON 浓度的增加，P-Drp-1、线粒体分裂蛋白 Mff 和 Fis-1 的表达水平升高，而 MFN1、MFN2 和 OPA1 的活性降低，导致自噬标记物 LC3 和 beclin-1 的表达增加。线粒体损伤和 ROS 生成之间的这种相互关系很明显，因为 ROS 可以引发线粒体的结构和功能缺陷。因此，受损的线粒体促进 ROS 的释放，从而加剧了损伤的循环，使整个过程恶化。使用特定的羟基、超氧阴离子抑制剂和钙螯合剂，我们的研究证实，ROS 和 Ca2+-介导的信号通路在 DON 诱导的 Drp1 磷酸化中起着重要作用。因此，ROS 和线粒体裂变抑制剂可为真菌毒素诱导的神经退行性疾病的药物开发提供重要的研究工具。
