title: Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium.
abstract: How cadmium (Cd) induces mitochondrial loss in the context of its hepatotoxic effects remains enigmatic. The purpose of the study was to investigate whether mitophagy contributes to mitochondrial loss in cadmium-induced hepatotoxicity and to determine the potential mechanism. In normal human liver L02 cells, we observed that Cd treatment led to a significant increase in LC3-II formation, the number of GFP-LC3 puncta and lysosomal colocalization with mitochondria. These results were associated with mitochondrial loss and bioenergetic deficit. Additionally, the abrogation of excessive mitophagy by ATG5 siRNA treatment efficiently suppressed the mitochondrial loss and cytotoxicity of Cd. Before overactivating mitophagy, Cd induced excessive mitochondrial fragmentation as a result of increasing dynamin 1-like (DNM1L) expression and enhancing the DNM1L mitochondrial translocation. Moreover, reversing the excessive mitochondrial fragmentation via the administration of DNM1L siRNA significantly inhibited the observed overactivation of mitophagy in Cd-induced hepatotoxicity. Notably, the selective DNM1L inhibitor Mdivi-1 blocked abnormal mitophagy and subsequently ameliorated Cd-induced hepatotoxicity in vivo. Together, our data indicated that Cd induces mitochondrial loss via the overactivation of mitophagy following DNM1L-dependent mitochondrial fragmentation. The balanced activity of DNM1L and mitophagy signaling may be a potential therapeutic approach to treat Cd-induced hepatotoxicity.
authors.affiliation: Department of Occupational Health; Third Military Medical University; Chongqing, China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Pi
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Pan
authors.initials: P
authors.lastname: Guo
authors.forename: Yuming
authors.initials: Y
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Xie
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.forename: Mindi
authors.initials: M
authors.lastname: He
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.forename: Linhong
authors.initials: L
authors.lastname: Deng
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D034281:Dynamins; D004734:Energy Metabolism / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D052999:Quinazolinones / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D052999:Quinazolinones; D034741:RNA, Small Interfering; D002104:Cadmium; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: DNM1L; cadmium; hepatotoxicity; mitochondrial fission; mitochondrial loss; mitophagy