2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline Alters Autophagosome Maturation, Cellular Lipidomic Profiles, and Expression of Core Pluripotent Factors
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline Alters Autophagosome Maturation, Cellular Lipidomic Profiles, and Expression of Core Pluripotent Factors
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2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉改变自噬体成熟、细胞脂质组学特征和核心多能因子的表达
DOI：
10.1021/acs.jafc.9b01041
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发表时间：
2019
影响因子：
6.1
通讯作者：
Liu Rong
中科院分区：
文献类型：
--
作者：
Song Dan;Guo Renpeng;Huang Haibo;Zheng Peixiang;Huang Hong;Oyang Qinqin;Xiao Xiaoyue;Wang Binran;Rong Jingtong;Liu Rong
2-氨基-3，8-二甲基咪唑并[4，5-f]喹喔啉（MeIQx）是人类饮食中发现的最丰富的杂环芳香胺（哈斯）之一，主要在高温烹饪肉类或鱼类时产生。虽然已将MeIQx作为潜在致癌物进行了研究，但其细胞毒性和相关分子机制仍不清楚。在这里，我们证明了自噬体成熟被MeIQx阻断。从机制上讲，MeIQx抑制溶酶体的酸化，而不是阻止自噬体-溶酶体融合。此外，MeIQx处理改变了细胞脂质谱。值得注意的是，许多磷脂和鞘脂在暴露于MeIQx后显著上调。此外，MeIQx降低小鼠胚胎干细胞（ESC）中多能性相关蛋白的表达。总之，MeIQx通过抑制溶酶体的酸化来阻断自噬体成熟，改变脂质代谢，并降低多能因子的表达。我们的研究提供了更多的细胞毒性证据，阐明了HAA暴露风险的相关机制，并有望促进食品安全和人类健康的监管。
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of the most abundant heterocyclic aromatic amines (HAAs) found in the human diet, is primarily produced during high-temperature meat or fish cooking. While MeIQx has been investigated as a potential carcinogen, the cytotoxicity and related molecular mechanisms remain unclear. Here, we demonstrate that autophagosome maturation is blocked by MeIQx. Mechanistically, MeIQx inhibits acidification of lysosomes rather than prevents autophagosome–lysosome fusion. Moreover, cellular lipid profiles are altered by MeIQx treatment. Notably, many phospholipids and sphingolipids are significantly upregulated after exposure to MeIQx. Furthermore, MeIQx decreases expression of pluripotency-associated proteins in mouse embryonic stem cells (ESCs). Together, MeIQx blocks autophagosome maturation through inhibiting acidification of lysosomes, alters lipid metabolism, and decreases expression of pluripotent factors. Our studies provide more cytotoxic evidence and elucidate related mechanisms on the risk of HAA exposure and are expected to promote supervision of food safety and human health.