Blocking reverse electron transfer-mediated mitochondrial DNA oxidation rescues cells from PANoptosis.

Autor: Shi FL; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Li Q; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Xu R; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Yuan LS; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Chen Y; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Shi ZJ; Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China., Li YP; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Zhou ZY; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Xu LH; Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China., Zha QB; Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China., Hu B; Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China. 42089537@qq.com., He XH; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. thexh@jnu.edu.cn.; Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China. thexh@jnu.edu.cn., Ou-Yang DY; Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. dongyun1967@aliyun.com.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Mar; Vol. 45 (3), pp. 594-608. Date of Electronic Publication: 2023 Nov 14.
DOI: 10.1038/s41401-023-01182-8
Abstrakt: PANoptosis is a new type of cell death featured with pyroptosis, apoptosis and necroptosis, and is implicated in organ injury and mortality in various inflammatory diseases, such as sepsis and hemophagocytic lymphohistiocytosis (HLH). Reverse electron transport (RET)-mediated mitochondrial reactive oxygen species (mtROS) has been shown to contribute to pyroptosis and necroptosis. In this study we investigated the roles of mtROS and RET in PANoptosis induced by TGF-β-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (Oxo) plus lipopolysaccharide (LPS) as well as the effects of anti-RET reagents on PANoptosis. We showed that pretreatment with anti-RET reagents 1-methoxy PMS (MPMS) or dimethyl fumarate (DMF) dose-dependently inhibited PANoptosis in macrophages BMDMs and J774A.1 cells induced by Oxo/LPS treatment assayed by propidium iodide (PI) staining. The three arms of the PANoptosis signaling pathway, namely pyroptosis, apoptosis and necroptosis signaling, as well as the formation of PANoptosomes were all inhibited by MPMS or DMF. We demonstrated that Oxo/LPS treatment induced RET and mtROS in BMDMs, which were reversed by MPMS or DMF pretreatment. Interestingly, the PANoptosome was co-located with mitochondria, in which the mitochondrial DNA was oxidized. MPMS and DMF fully blocked the mtROS production and the formation of PANoptosome induced by Oxo plus LPS treatment. An HLH mouse model was established by poly(I:C)/LPS challenge. Pretreatment with DMF (50 mg·kg -1 ·d -1 , i.g. for 3 days) or MPMS (10 mg·kg -1 ·d -1 , i.p. for 2 days) (DMF i.g. MPMS i.p.) effectively alleviated HLH lesions accompanied by decreased hallmarks of PANoptosis in the liver and kidney. Collectively, RET and mtDNA play crucial roles in PANoptosis induction and anti-RET reagents represent a novel class of PANoptosis inhibitors by blocking oxidation of mtDNA, highlighting their potential application in treating PANoptosis-related inflammatory diseases. PANoptotic stimulation induces reverse electron transport (RET) and reactive oxygen species (ROS) in mitochondia, while 1-methoxy PMS and dimethyl fumarate can inhibit PANoptosis by suppressing RETmediated oxidation of mitochondrial DNA.
(© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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