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Mitochondrial uptake of aristolactam I plays a critical role in its toxicity
Toxicology Letters ( IF 2.9 ) Pub Date : 2024-02-28 , DOI: 10.1016/j.toxlet.2024.02.013 Yan Zhou 1 , Ruirui Cui 2 , Mingkang Zhang 3 , Fabing Tang 4 , Xiaohua Ma 1 , Xin'an Wu 1
Toxicology Letters ( IF 2.9 ) Pub Date : 2024-02-28 , DOI: 10.1016/j.toxlet.2024.02.013 Yan Zhou 1 , Ruirui Cui 2 , Mingkang Zhang 3 , Fabing Tang 4 , Xiaohua Ma 1 , Xin'an Wu 1
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Aristolochic acid I (AAI), a component of aristolochic acids, can be converted to the toxic metabolite Aristolactam I (ALI) which forms aristolactam-nitrenium with delocalized positive charges. It is widely accepted that delocalized lipophilic cations can accumulate in mitochondria due to the highly negatively charged microenvironment of the mitochondrial matrix, but the uptake of ALI by mitochondria is not known. In this study, the cell uptake and mitochondrial localization of ALI, and its subsequent impact on mitochondrial function were investigated. Results show that ALI can rapidly penetrate HK-2 cells without relying on organic anion transporters 1/3 (OAT1/3). The cellular distribution of ALI was found to align with the observed distribution of a mitochondria-selective dye in HK-2 cells. Furthermore, the cell uptake and mitochondrial uptake of ALI were both inhibited by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, which induces mitochondrial membrane depolarization. These results suggest that ALI is selectively taken up by mitochondria. Consequently, mitochondrial dysfunction was observed after treatment with ALI. It should be noted that inhibiting OAT1/3 could result in an increased exposure of ALI in vivo and cause more seriously nephrotoxicity. In conclusion, this research reports the mitochondrial uptake of ALI and provides new insight on potential strategies for protection against AAI-induced nephrotoxicity.
中文翻译：
马兜铃内酰胺 I 的线粒体摄取对其毒性起着关键作用
马兜铃酸 I (AAI) 是马兜铃酸的一种成分，可转化为有毒代谢物马兜铃内酰胺 I (ALI)，形成带有离域正电荷的马兜铃内酰胺-氮。人们普遍认为，由于线粒体基质的高负电荷微环境，离域亲脂性阳离子可以在线粒体中积聚，但线粒体对 ALI 的吸收尚不清楚。在本研究中，研究了 ALI 的细胞摄取和线粒体定位及其对线粒体功能的后续影响。结果表明，ALI无需依赖有机阴离子转运蛋白1/3（OAT1/3）即可快速穿透HK-2细胞。研究发现 ALI 的细胞分布与 HK-2 细胞中观察到的线粒体选择性染料的分布一致。此外，细胞摄取和线粒体摄取ALI均受到羰基氰化物4-(三氟甲氧基)苯腙的抑制，从而诱导线粒体膜去极化。这些结果表明 ALI 被线粒体选择性吸收。因此，ALI 治疗后观察到线粒体功能障碍。值得注意的是，抑制OAT1/3可能导致体内ALI暴露增加，并引起更严重的肾毒性。总之，本研究报告了 ALI 的线粒体摄取情况，并为预防 AAI 诱导的肾毒性的潜在策略提供了新的见解。
更新日期：2024-02-28
中文翻译：
马兜铃内酰胺 I 的线粒体摄取对其毒性起着关键作用
马兜铃酸 I (AAI) 是马兜铃酸的一种成分，可转化为有毒代谢物马兜铃内酰胺 I (ALI)，形成带有离域正电荷的马兜铃内酰胺-氮。人们普遍认为，由于线粒体基质的高负电荷微环境，离域亲脂性阳离子可以在线粒体中积聚，但线粒体对 ALI 的吸收尚不清楚。在本研究中，研究了 ALI 的细胞摄取和线粒体定位及其对线粒体功能的后续影响。结果表明，ALI无需依赖有机阴离子转运蛋白1/3（OAT1/3）即可快速穿透HK-2细胞。研究发现 ALI 的细胞分布与 HK-2 细胞中观察到的线粒体选择性染料的分布一致。此外，细胞摄取和线粒体摄取ALI均受到羰基氰化物4-(三氟甲氧基)苯腙的抑制，从而诱导线粒体膜去极化。这些结果表明 ALI 被线粒体选择性吸收。因此，ALI 治疗后观察到线粒体功能障碍。值得注意的是，抑制OAT1/3可能导致体内ALI暴露增加，并引起更严重的肾毒性。总之，本研究报告了 ALI 的线粒体摄取情况，并为预防 AAI 诱导的肾毒性的潜在策略提供了新的见解。
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