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Volume 13
Issue 9
10.3390/toxics13090736
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Article

Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1–RIPK3–MLKL Axis

by
Peng Zhou
1,2,†,
Jiankang Xuan
1,†,
Weixiao Xu
1,†,
Di An
1,
Sining Meng
1,
Hongchao Zhang
3,
Miaoyang Hu
4,
Wanqingyang Hui
5,
Yifei Wang
1,
Jie Cheng
3,
Jianping Xiong
3,
Jun Wang
3,5,* and
Xufeng Chen
1,*
1
Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
2
Department of Emergency Medicine, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
3
Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
4
Department of Hygienic Analysis and Detection, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China
5
The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Toxics 2025, 13(9), 736; https://doi.org/10.3390/toxics13090736 (registering DOI)
Submission received: 29 July 2025 / Revised: 24 August 2025 / Accepted: 27 August 2025 / Published: 30 August 2025
(This article belongs to the Section Drugs Toxicity)
Versions Notes

Abstract

Methamphetamine (Meth), a psychostimulant drug of the amphetamine type, is widely abused and highly neurotoxic. Meth exposure leads to neuronal necroptosis, and the mitochondrial dysfunction may be involved. However, the underlying mechanisms remain poorly understood. Here, we found that Meth significantly elicited the formation of the RIPK1–RIPK3–MLKL necrosome complex. Intriguingly, the activated MLKL (p-MLKL) translocated to the mitochondrial membrane and displayed pore-forming activity, manifesting as the penetration of MLKL in the cell membranes of the mitochondria, which caused decreased mitochondrial membrane potential, ATP generation, and mitochondrial DNA (mtDNA) and increased mitochondrial ROS (mtROS) generation, which finalized neuronal necroptosis. Notably, MLKL activation and translocation seem to depend on the RIPK1–RIPK3 axis since these adverse effects can be substantially ameliorated by disruption of the necrosome complex formation by the necroptotic inhibitor 1 (Nec-1), which also markedly impeded the MLKL mitochondrial membrane translocation. Finally, to delineate the effects of pore formation-associated ROS generation, specific blockage of mtROS retarded the Meth-induced neuronal necroptosis. In conclusion, our study reveals for the first time that MLKL mitochondrial membrane translocation may be involved in Meth-induced neuronal necroptosis. Therefore, impeding MLKL translocation might provide a novel therapeutic strategy for Meth-induced neurotoxicity.
Keywords: Meth; Mitochondrial dysfunction; neuronal necroptosis; RIPK1–RIPK3–MLKL axis Meth; Mitochondrial dysfunction; neuronal necroptosis; RIPK1–RIPK3–MLKL axis

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MDPI and ACS Style

Zhou, P.; Xuan, J.; Xu, W.; An, D.; Meng, S.; Zhang, H.; Hu, M.; Hui, W.; Wang, Y.; Cheng, J.; et al. Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1–RIPK3–MLKL Axis. Toxics 2025, 13, 736. https://doi.org/10.3390/toxics13090736

AMA Style

Zhou P, Xuan J, Xu W, An D, Meng S, Zhang H, Hu M, Hui W, Wang Y, Cheng J, et al. Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1–RIPK3–MLKL Axis. Toxics. 2025; 13(9):736. https://doi.org/10.3390/toxics13090736

Chicago/Turabian Style

Zhou, Peng, Jiankang Xuan, Weixiao Xu, Di An, Sining Meng, Hongchao Zhang, Miaoyang Hu, Wanqingyang Hui, Yifei Wang, Jie Cheng, and et al. 2025. "Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1–RIPK3–MLKL Axis" Toxics 13, no. 9: 736. https://doi.org/10.3390/toxics13090736

APA Style

Zhou, P., Xuan, J., Xu, W., An, D., Meng, S., Zhang, H., Hu, M., Hui, W., Wang, Y., Cheng, J., Xiong, J., Wang, J., & Chen, X. (2025). Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1–RIPK3–MLKL Axis. Toxics, 13(9), 736. https://doi.org/10.3390/toxics13090736

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