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线粒体功能障碍诱发的二氢乳清酸脱氢酶乙酰化在顺铂诱导的急性肾损伤期间的肾细胞铁死亡中起作用。

Mitochondrial Dysfunction-Evoked DHODH Acetylation is Involved in Renal Cell Ferroptosis during Cisplatin-Induced Acute Kidney Injury.

机构信息

Department of Toxicology, Anhui Medical University, Hefei, China, 230032.

Department of Urology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China, 230601.

出版信息

Adv Sci (Weinh). 2024 Nov;11(43):e2404753. doi: 10.1002/advs.202404753. Epub 2024 Sep 20.

DOI:10.1002/advs.202404753
PMID:39303219
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11578349/
Abstract

Several studies have observed renal cell ferroptosis during cisplatin-induced acute kidney injury (AKI). However, the mechanism is not completely clear. In this study, oxidized arachidonic acid (AA) metabolites are increased in cisplatin-treated HK-2 cells. Targeted metabolomics showed that the end product of pyrimidine biosynthesis is decreased and the initiating substrate of pyrimidine biosynthesis is increased in cisplatin-treated mouse kidneys. Mitochondrial DHODH, a key enzyme for pyrimidine synthesis, and its downstream product CoQH, are downregulated. DHODH overexpression attenuated but DHODH silence exacerbated cisplatin-induced CoQH depletion and lipid peroxidation. Mechanistically, renal DHODH acetylation is elevated in cisplatin-exposed mice. Mitochondrial SIRT3 is reduced in cisplatin-treated mouse kidneys and HK-2 cells. Both in vitro SIRT3 overexpression and in vivo NMN supplementation attenuated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis. By contrast, Sirt3 knockout aggravated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis, which can not be attenuated by NMN. Additional experiments showed that cisplatin caused mitochondrial dysfunction and SIRT3 SUMOylation. Pretreatment with mitochondria-target antioxidant MitoQ alleviated cisplatin-caused mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. MitoQ pretreatment protected against cisplatin-caused AKI and renal cell ferroptosis. Taken together, these results suggest that mitochondrial dysfunction-evoked DHODH acetylation partially contributes to renal cell ferroptosis during cisplatin-induced AKI.

摘要

几项研究观察到顺铂诱导的急性肾损伤 (AKI) 期间肾细胞发生铁死亡。然而，其机制尚不完全清楚。在这项研究中，在顺铂处理的 HK-2 细胞中，氧化花生四烯酸 (AA) 代谢物增加。靶向代谢组学显示，嘧啶生物合成的终产物在顺铂处理的小鼠肾脏中减少，嘧啶生物合成的起始底物增加。嘧啶合成的关键酶线粒体二氢乳清酸脱氢酶 (DHODH) 及其下游产物 CoQH 下调。DHODH 过表达可减轻，但 DHODH 沉默可加重顺铂诱导的 CoQH 耗竭和脂质过氧化。在机制上，顺铂暴露的小鼠肾脏中 DHODH 乙酰化水平升高。在顺铂处理的小鼠肾脏和 HK-2 细胞中，线粒体 SIRT3 减少。体外 SIRT3 过表达和体内 NMN 补充均可减轻顺铂诱导的线粒体 DHODH 乙酰化和肾细胞铁死亡。相反，Sirt3 敲除加重了顺铂诱导的线粒体 DHODH 乙酰化和肾细胞铁死亡，而 NMN 不能减轻这种加重作用。额外的实验表明，顺铂导致线粒体功能障碍和 SIRT3 SUMO 化。线粒体靶向抗氧化剂 MitoQ 预处理可减轻顺铂引起的线粒体功能障碍、SIRT3 SUMO 化和 DHODH 乙酰化。MitoQ 预处理可预防顺铂引起的 AKI 和肾细胞铁死亡。综上所述，这些结果表明，线粒体功能障碍引起的 DHODH 乙酰化部分导致顺铂诱导的 AKI 期间肾细胞发生铁死亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/c103cf0df588/ADVS-11-2404753-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/b0945d6a8ddb/ADVS-11-2404753-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/483dafa395b0/ADVS-11-2404753-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/c103cf0df588/ADVS-11-2404753-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/aaf3354d4645/ADVS-11-2404753-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/19bdc3555995/ADVS-11-2404753-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/caf809dfcdce/ADVS-11-2404753-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/f2363c512cdc/ADVS-11-2404753-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/d9e6a1a12065/ADVS-11-2404753-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/b0945d6a8ddb/ADVS-11-2404753-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/483dafa395b0/ADVS-11-2404753-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/119a/11578349/c103cf0df588/ADVS-11-2404753-g010.jpg

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