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27.04.2024 | Article

ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes

verfasst von: Jingfang Chen, Qi Feng, Yingjin Qiao, Shaokang Pan, Lulu Liang, Yong Liu, Xiaonan Zhang, Dongwei Liu, Zhihong Liu, Zhangsuo Liu

Erschienen in: Diabetologia

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Abstract

Aims

Lactate accumulation is reported to be a biomarker for diabetic nephropathy progression. Lactate drives lysine lactylation, a newly discovered post-translational modification that is involved in the pathogenesis of cancers and metabolic and inflammatory disease. Here, we aimed to determine whether lysine lactylation is involved in the pathogenesis of diabetic nephropathy.

Methods

Renal biopsy samples from individuals with diabetic nephropathy (n=22) and control samples from individuals without diabetes and kidney disease (n=9) were obtained from the First Affiliated Hospital of Zhengzhou University for immunohistochemical staining. In addition, we carried out global lactylome profiling of kidney tissues from db/m and db/db mice using LC-MS/MS. Furthermore, we assessed the role of lysine lactylation and acyl-CoA synthetase family member 2 (ACSF2) in mitochondrial function in human proximal tubular epithelial cells (HK-2).

Results

The expression level of lysine lactylation was significantly increased in the kidneys of individuals with diabetes as well as in kidneys from db/db mice. Integrative lactylome analysis of the kidneys of db/db and db/m mice identified 165 upregulated proteins and 17 downregulated proteins, with an increase in 356 lysine lactylation sites and a decrease in 22 lysine lactylation sites decreased. Subcellular localisation analysis revealed that most lactylated proteins were found in the mitochondria (115 proteins, 269 sites). We further found that lactylation of the K182 site in ACSF2 contributes to mitochondrial dysfunction. Finally, the expression of ACSF2 was notably increased in the kidneys of db/db mice and individuals with diabetic nephropathy.

Conclusions

Our study strongly suggests that lysine lactylation and ACSF2 are mediators of mitochondrial dysfunction and may contribute to the progression of diabetic nephropathy.

Data availability

The LC-MS/MS proteomics data have been deposited in the ProteomeXchange Consortium database (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD050070.

Graphical Abstract

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Umanath K, Lewis JB (2018) Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis 71(6):884–895. https://doi.org/10.1053/j.ajkd.2017.10.026CrossRefPubMed

Cheng HT, Xu X, Lim PS, Hung KY (2021) Worldwide epidemiology of diabetes-related end-stage renal disease, 2000–2015. Diabetes Care 44(1):89–97. https://doi.org/10.2337/dc20-1913CrossRefPubMed

Fioretto P, Pontremoli R (2022) Expanding the therapy options for diabetic kidney disease. Nat Rev Nephrol 18(2):78–79. https://doi.org/10.1038/s41581-021-00522-3CrossRefPubMed

Lee DY, Kim JY, Ahn E et al (2022) Associations between local acidosis induced by renal LDHA and renal fibrosis and mitochondrial abnormalities in patients with diabetic kidney disease. Transl Res 249:88–109. https://doi.org/10.1016/j.trsl.2022.06.015CrossRefPubMed

Kugathasan L, Darshi M, Srinivasan Sridhar V et al (2023) 12-OR: Urine lactate is a disease biomarker for diabetic kidney disease. Diabetes 72(Supplement_1):12-OR. https://doi.org/10.2337/db23-12-ORCrossRef

Azushima K, Kovalik JP, Yamaji T et al (2023) Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy. Kidney Int 104(6):1135–1149. https://doi.org/10.1016/j.kint.2023.08.006CrossRefPubMed

Wang N, Wang W, Wang X et al (2022) Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ Res 131(11):893–908. https://doi.org/10.1161/circresaha.122.320488CrossRefPubMed

Xiong J, He J, Zhu J et al (2022) Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell 82(9):1660-1677.e10. https://doi.org/10.1016/j.molcel.2022.02.033CrossRefPubMed

Yu J, Chai P, Xie M et al (2021) Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol 22(1):85. https://doi.org/10.1186/s13059-021-02308-zCrossRefPubMedPubMedCentral

10.

Zhang D, Tang Z, Huang H et al (2019) Metabolic regulation of gene expression by histone lactylation. Nature 574(7779):575–580. https://doi.org/10.1038/s41586-019-1678-1CrossRefPubMedPubMedCentral

11.

Xie B, Lin J, Chen X et al (2023) CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer. Mol Cancer 22(1):151. https://doi.org/10.1186/s12943-023-01856-1CrossRefPubMedPubMedCentral

12.

Jia M, Yue X, Sun W et al (2023) ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Sci Adv 9(22):eadg4993. https://doi.org/10.1126/sciadv.adg4993CrossRefPubMedPubMedCentral

13.

Irizarry-Caro RA, McDaniel MM, Overcast GR, Jain VG, Troutman TD, Pasare C (2020) TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc Natl Acad Sci U S A 117(48):30628–30638. https://doi.org/10.1073/pnas.2009778117CrossRefPubMedPubMedCentral

14.

Wang J, Yang P, Yu T et al (2022) Lactylation of PKM2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages. Int J Biol Sci 18(16):6210–6225. https://doi.org/10.7150/ijbs.75434CrossRefPubMedPubMedCentral

15.

Yang Z, Yan C, Ma J et al (2023) Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab 5(1):61–79. https://doi.org/10.1038/s42255-022-00710-wCrossRefPubMed

16.

Yang D, Yin J, Shan L, Yi X, Zhang W, Ding Y (2022) Identification of lysine-lactylated substrates in gastric cancer cells. iScience 25(7):104630. https://doi.org/10.1016/j.isci.2022.104630CrossRefPubMedPubMedCentral

17.

Wang X, Fan W, Li N et al (2023) YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2. Genome Biol 24(1):87. https://doi.org/10.1186/s13059-023-02931-yCrossRefPubMedPubMedCentral

18.

An S, Yao Y, Hu H et al (2023) PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation. Cell Death Dis 14(7):457. https://doi.org/10.1038/s41419-023-05952-4CrossRefPubMedPubMedCentral

19.

Xue M, Fang T, Sun H et al (2021) PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation. Cell Death Dis 12(12):1107. https://doi.org/10.1038/s41419-021-04408-xCrossRefPubMedPubMedCentral

20.

Gan B (2021) Mitochondrial regulation of ferroptosis. J Cell Biol 220(9):e202105043. https://doi.org/10.1083/jcb.202105043CrossRefPubMedPubMedCentral

21.

Gao M, Yi J, Zhu J et al (2019) Role of mitochondria in ferroptosis. Mol Cell 73(2):354-363.e353. https://doi.org/10.1016/j.molcel.2018.10.042CrossRefPubMed

22.

Naaman SC, Bakris GL (2023) Diabetic nephropathy: update on pillars of therapy slowing progression. Diabetes Care 46(9):1574–1586. https://doi.org/10.2337/dci23-0030CrossRefPubMed

23.

Forbes JM, Thorburn DR (2018) Mitochondrial dysfunction in diabetic kidney disease. Nat Rev Nephrol 14(5):291–312. https://doi.org/10.1038/nrneph.2018.9CrossRefPubMed

24.

Han Y, Xu X, Tang C et al (2018) Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis. Redox Biol 16:32–46. https://doi.org/10.1016/j.redox.2018.02.013CrossRefPubMedPubMedCentral

25.

Li Q, Liao J, Chen W et al (2022) NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway. Free Radic Biol Med 187:158–170. https://doi.org/10.1016/j.freeradbiomed.2022.05.024CrossRefPubMed

26.

Jiang N, Zhao H, Han Y et al (2020) HIF-1α ameliorates tubular injury in diabetic nephropathy via HO-1-mediated control of mitochondrial dynamics. Cell Prolif 53(11):e12909. https://doi.org/10.1111/cpr.12909CrossRefPubMedPubMedCentral

27.

Liu L, Bai F, Song H et al (2022) Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy. Redox Biol 50:102260. https://doi.org/10.1016/j.redox.2022.102260CrossRefPubMedPubMedCentral

28.

Yang K, Fan M, Wang X et al (2022) Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ 29(1):133–146. https://doi.org/10.1038/s41418-021-00841-9CrossRefPubMed

29.

Stockwell BR (2022) Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185(14):2401–2421. https://doi.org/10.1016/j.cell.2022.06.003CrossRefPubMedPubMedCentral

30.

Fang X, Ardehali H, Min J, Wang F (2022) The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol 20(1):7–23. https://doi.org/10.1038/s41569-022-00735-4CrossRefPubMedPubMedCentral

31.

Wang H, Cheng Y, Mao C et al (2021) Emerging mechanisms and targeted therapy of ferroptosis in cancer. Mol Ther 29(7):2185–2208. https://doi.org/10.1016/j.ymthe.2021.03.022CrossRefPubMedPubMedCentral

32.

Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282. https://doi.org/10.1038/s41580-020-00324-8CrossRefPubMedPubMedCentral

33.

Guo R, Duan J, Pan S et al (2023) The road from AKI to CKD: molecular mechanisms and therapeutic targets of ferroptosis. Cell Death Dis 14(7):426. https://doi.org/10.1038/s41419-023-05969-9CrossRefPubMedPubMedCentral

34.

Zhao Z, Wu J, Xu H et al (2020) XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia-reperfusion injury. Cell Death Dis 11(8):629. https://doi.org/10.1038/s41419-020-02871-6CrossRefPubMedPubMedCentral

35.

Tonnus W, Meyer C, Steinebach C et al (2021) Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat Commun 12(1):4402. https://doi.org/10.1038/s41467-021-24712-6CrossRefPubMedPubMedCentral

36.

Wang J, Liu Y, Wang Y, Sun L (2021) The cross-link between ferroptosis and kidney diseases. Oxid Med Cell Longev 2021:6654887. https://doi.org/10.1155/2021/6654887CrossRefPubMedPubMedCentral

37.

Li S, Zheng L, Zhang J, Liu X, Wu Z (2021) Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy. Free Radic Biol Med 162:435–449. https://doi.org/10.1016/j.freeradbiomed.2020.10.323CrossRefPubMed

38.

Kim S, Kang SW, Joo J et al (2021) Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis 12(2):160. https://doi.org/10.1038/s41419-021-03452-xCrossRefPubMedPubMedCentral

39.

Watkins PA, Maiguel D, Jia Z, Pevsner J (2007) Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res 48(12):2736–2750. https://doi.org/10.1194/jlr.M700378-JLR200CrossRefPubMed

40.

Luo L, Zhang S, Guo N, Li H, He S (2023) ACSF2-mediated ferroptosis is involved in ulcerative colitis. Life Sci 313:121272. https://doi.org/10.1016/j.lfs.2022.121272CrossRefPubMed

41.

Wu MN, Zhou DM, Jiang CY et al (2022) Genetic analysis of potential biomarkers and therapeutic targets in ferroptosis from psoriasis. Front Immunol 13:1104462. https://doi.org/10.3389/fimmu.2022.1104462CrossRefPubMed

42.

Shi H, Qi H, Xie D et al (2023) Inhibition of ACSF2 protects against renal ischemia/reperfusion injury via mediating mitophagy in proximal tubular cells. Free Radic Biol Med 198:68–82. https://doi.org/10.1016/j.freeradbiomed.2023.02.003CrossRefPubMed

43.

Wang M, Su Y, Hou C et al (2022) Targeted lipidomics analysis of lysine 179 acetylation of ACSF2 in rat hepatic stellate cells. Prostaglandins Other Lipid Mediat 163:106671. https://doi.org/10.1016/j.prostaglandins.2022.106671CrossRefPubMed

Titel: ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes
verfasst von: Jingfang Chen
Qi Feng
Yingjin Qiao
Shaokang Pan
Lulu Liang
Yong Liu
Xiaonan Zhang
Dongwei Liu
Zhihong Liu
Zhangsuo Liu
Publikationsdatum: 27.04.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-024-06156-x

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