ZDHHC8-mediated S-palmitoylation of RAD21 causes mitochondrial dysfunction in diabetic nephropathy via inhibiting ACSM3 transcription.

IF 13.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation Pub Date : 2026-07-15 DOI:10.1038/s41418-026-01816-4

Wei Chen, Yinyin Chen, Shaobin Duan, Hao Li, Yang Gao, Weiying Zhang, Guoyong Liu, Jiayi Wang, Xiaofei Peng, Liyu He

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Abstract

Tubulointerstitial injury exerts a key role in diabetic nephropathy (DN) development; however, its potential mechanism is still unclear. We explored the role and molecular mechanisms of RAD21 cohesin complex component (RAD21) in mitochondrial dysfunction during tubulointerstitial injury of DN. We found that RAD21 was down-regulated, but its S-palmitoylation level was up-regulated in DN. RAD21 overexpression attenuated renal tubulointerstitial injury, fibrosis and mitochondrial dysfunction in DN. In addition, zinc finger DHHC-type palmitoyltransferase8 (ZDHHC8) served as a key acetyltransferase that catalyzed RAD21 S-palmitoylation at C78 site, which led to heat shock protein member 8 (HSPA8)-mediated lysosomal degradation of RAD21. Down-regulation of RAD21 repressed the transcription and expression of ACSM3. ACSM3 deficiency abrogated the beneficial effect of RAD21 overexpression on mitochondrial dysfunction during tubulointerstitial injury in DN. In conclusion, ZDHHC8-mediated S-palmitoylation of RAD21 favored its lysosomal degradation with assistance of HSPA8, which repressed ACSM3 transcription to cause mitochondrial dysfunction, thereby accelerating DN progression.

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zdhhc8介导的s -棕榈酰化RAD21通过抑制ACSM3转录导致糖尿病肾病的线粒体功能障碍。

小管间质损伤在糖尿病肾病（DN）发展中起关键作用然而，其潜在机制尚不清楚。我们探讨了RAD21黏结蛋白复合物（RAD21）在DN小管间质损伤时线粒体功能障碍中的作用及其分子机制。我们发现RAD21在DN中下调，但其s -棕榈酰化水平上调。RAD21过表达可减轻DN患者肾小管间质损伤、纤维化和线粒体功能障碍。此外，锌指DHHC-type palmitoyltransferase8 （ZDHHC8）作为关键的乙酰转移酶，在C78位点催化RAD21 s -棕榈酰化，导致热休克蛋白成员8 （HSPA8）介导的RAD21溶酶体降解。RAD21的下调抑制ACSM3的转录和表达。ACSM3缺失使RAD21过表达对DN小管间质损伤时线粒体功能障碍的有益作用消失。综上所述，zdhhc8介导的RAD21的s -棕榈酰化在HSPA8的帮助下有利于其溶酶体降解，从而抑制ACSM3转录导致线粒体功能障碍，从而加速DN的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death and Differentiation 生物-生化与分子生物学

CiteScore

24.70

自引率

1.60%

发文量

181

审稿时长

3 months

期刊介绍： Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.