Mitophagy-regulated Necroptosis plays a vital role in the nephrotoxicity of Fumonisin B1 in vivo and in vitro

Zhang Ping; Zhang Shuxia; Du Xinyu; Huang Kehe; Chen Xingxiang; Wang Chunfeng

doi:10.1016/j.fct.2024.114714

Mitophagy-regulated Necroptosis plays a vital role in the nephrotoxicity of Fumonisin B1 in vivo and in vitro

Food Chem Toxicol. 2024 May 3:189:114714. doi: 10.1016/j.fct.2024.114714. Online ahead of print.

Authors

Zhang Ping¹, Zhang Shuxia¹, Du Xinyu¹, Huang Kehe¹, Chen Xingxiang², Wang Chunfeng³

Affiliations

¹ College of Veterinary Medicine, Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China.
² College of Veterinary Medicine, Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China. Electronic address: cxx@njau.edu.cn.
³ College of Animal Medicine, Jilin Agricultural University, Changchun, 130118, Jilin Province, China. Electronic address: wangchunfeng@jlau.edu.cn.

PMID: 38705344
DOI: 10.1016/j.fct.2024.114714

Abstract

Fumonisin B1 (FB1), one of the most widely distributed mycotoxins found in grains and feeds as contaminants, affects many organs including the kidney once ingested. However, the nephrotoxicity of FB1 remains to be further uncovered. The connection between necroptosis and nephrotoxicity of FB1 has been investigated in this study. The results showed that mice exposed to high doses of FB1 (2.25 mg/kg b.w.) developed kidney damage, with significant increases in proinflammatory cytokines (Il-6, Il-1β), kidney injury-related markers (Ngal, Ntn-1), and gene expressions linked to necroptosis (Ripk1, Ripk3, Mlkl). The concentration-dependent damage effects of FB1 on PK-15 cells contain cytotoxicity, cellular inflammatory response, and necroptosis. These FB1-induced effects can be neutralized by pretreatment with the necroptosis inhibitor Nec-1. Additionally, FB1 caused mitochondrial damage and mitophagy in vivo and in vitro, whereas Mdivi-1, a mitophagy inhibitor, prevented these effects on PK-15 cells as well as, more crucially, necroptosis. In conclusion, the RIPK1/RIPK3/MLKL signal route of necroptosis, which may be controlled by mitophagy, mediated nephrotoxicity of FB1. Our findings clarify the underlying molecular pathways of FB1-induced nephrotoxicity.

Keywords: Fumonisin B1; Mitophagy; Necroptosis; Nephrotoxicity; RIPK1/RIPK3/MLKL.