Graphene quantum dots (GQDs) provide a bright prospect in the biomedical application because they contain low-toxic compounds and promise imaging of deep tissues and tiny vascular structures. However, the biosafety of this novel QDs has not been thoroughly evaluated, especially in the central nervous system (CNS). The microarray analysis provides a hint that nitrogen-doped GQDs (N-GQDs) exposure could cause ferroptosis in microglia, which is a novel form of cell death dependent on iron overload and lipid peroxidation. The cytosolic iron overload, glutathione (GSH) depletion, excessive reactive oxygen species (ROS) production and lipid peroxidation (LPO) were observed in microglial BV2 cells treated with N-GQDs, which indicated that N-GQDs could damage the iron metabolism and redox balance in microglia. The pre-treatments of a specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) and an iron chelater Deferoxamine mesylate (DFO) not only inhibited cell death, but also alleviated iron overload, LPO and alternations in ferroptosis biomarkers in microglia, which were caused by N-GQDs. When assessing the potential mechanisms of N-GQDs causing ferroptosis in microglia, we found that the iron content, ROS generation and LPO level in mitochondria of BV2 cells all enhanced after N-GQDs exposure. When the antioxidant ability of mitochondria was increased by the pre-treatment of a mitochondria targeted ROS scavenger MitoTEMPO, the ferroptotic biological changes were effectively reversed in BV2 cells treated with N-GQDs, which indicated that the N-GQDs-induced ferroptosis in microglia could be attributed to the mitochondrial oxidative stress. Additionally, amino functionalized GQDs (A-GQDs) elicited milder redox imbalance in mitochondria and resulted in less ferroptotic effects than N-GQDs in microglia, which suggested a slight protection of amino group functionalization in GQDs causing ferroptosis. N-GQDs exposure caused ferroptosis in microglia via inducing mitochondrial oxidative stress, and the ferroptotic effects induced by A-GQDs were milder than N-GQDs when the exposure method is same. This study will not only provide new insights in the GQDs-induced cell damage performed in multiple types of cell death, but also in the influence of chemical modification on the toxicity of GQDs.

中文翻译：

---

通过小胶质细胞中的线粒体氧化应激对石墨烯量子点的响应而引起的肥大作用。

石墨烯量子点（GQD）在生物医学应用中提供了光明的前景，因为它们包含低毒化合物，并有望对深部组织和微小血管结构进行成像。但是，这种新型量子点的生物安全性尚未得到彻底评估，尤其是在中枢神经系统（CNS）中。微阵列分析提供了一个暗示，即氮掺杂的GQDs（N-GQDs）暴露可能导致小胶质细胞的肥大症，这是一种新的细胞死亡形式，取决于铁超载和脂质过氧化作用。N-GQDs处理的小胶质BV2细胞中观察到胞质铁超载，谷胱甘肽（GSH）耗竭，过量的活性氧（ROS）产生和脂质过氧化（LPO），这表明N-GQDs可能会破坏铁的代谢和氧化还原小胶质细胞平衡。特定的铁素体抑制因子Ferrostatin-1（Fer-1）和铁螯合剂Deferoxamine甲磺酸盐（DFO）的预处理不仅可以抑制细胞死亡，还可以缓解铁超载，LPO和小胶质细胞中铁素体肥大生物标志物的改变。通过N-GQD。在评估N-GQD引起小胶质细胞肥大症的潜在机制时，我们发现N-GQDs暴露后，BV2细胞线粒体中的铁含量，ROS生成和LPO水平均增强。当线粒体靶向ROS清除剂MitoTEMPO的预处理提高了线粒体的抗氧化能力时，用N-GQDs处理过的BV2细胞中的促铁素体生物学改变被有效逆转，这表明N-GQDs诱导的小胶质细胞铁素体病可以归因于线粒体的氧化应激。另外，与小胶质细胞中的N-GQD相比，氨基官能化的GQD（A-GQDs）在线粒体中引起了较轻的氧化还原失衡，并导致了促铁作用，这表明GQD中的氨基官能化作用受到轻微的保护，从而导致了铁定病。N-GQDs的暴露通过诱导线粒体氧化应激而引起小胶质细胞的肥大病，在相同的暴露方法下，A-GQDs引起的肥大作用比N-GQDs温和。这项研究不仅将为多种类型的细胞死亡中GQD诱导的细胞损伤提供新的见解，而且还将提供化学修饰对GQD毒性的影响的新见解。这提示在导致铁锈病的GQD中，氨基官能团的保护作用较弱。N-GQDs的暴露通过诱导线粒体氧化应激而引起小胶质细胞的肥大病，在相同的暴露方法下，A-GQDs引起的肥大作用比N-GQDs温和。这项研究不仅将为多种类型的细胞死亡中GQD诱导的细胞损伤提供新的见解，而且还将提供化学修饰对GQD毒性的影响的新见解。这提示在导致铁锈病的GQD中，氨基官能团的保护作用较弱。N-GQDs的暴露通过诱导线粒体氧化应激而引起小胶质细胞的肥大病，在相同的暴露方法下，A-GQDs引起的肥大作用比N-GQDs温和。这项研究不仅将为多种类型的细胞死亡中GQD诱导的细胞损伤提供新的见解，而且还将提供化学修饰对GQD毒性的影响的新见解。