{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T04:59:49Z","timestamp":1787374789065,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:00:00Z","timestamp":1756512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82472240"],"award-info":[{"award-number":["82472240"]}]},{"name":"National Natural Science Foundation of China","award":["82473664"],"award-info":[{"award-number":["82473664"]}]},{"name":"National Natural Science Foundation of China","award":["22KJA330001"],"award-info":[{"award-number":["22KJA330001"]}]},{"name":"National Natural Science Foundation of China","award":["2022-29"],"award-info":[{"award-number":["2022-29"]}]},{"name":"Major Projects of Natural Science Foundation in Jiangsu Higher Education Institutions of China","award":["82472240"],"award-info":[{"award-number":["82472240"]}]},{"name":"Major Projects of Natural Science Foundation in Jiangsu Higher Education Institutions of China","award":["82473664"],"award-info":[{"award-number":["82473664"]}]},{"name":"Major Projects of Natural Science Foundation in Jiangsu Higher Education Institutions of China","award":["22KJA330001"],"award-info":[{"award-number":["22KJA330001"]}]},{"name":"Major Projects of Natural Science Foundation in Jiangsu Higher Education Institutions of China","award":["2022-29"],"award-info":[{"award-number":["2022-29"]}]},{"name":"Young and Middle-aged Academic Leaders of \u201cBlue Project\u201d","award":["82472240"],"award-info":[{"award-number":["82472240"]}]},{"name":"Young and Middle-aged Academic Leaders of \u201cBlue Project\u201d","award":["82473664"],"award-info":[{"award-number":["82473664"]}]},{"name":"Young and Middle-aged Academic Leaders of \u201cBlue Project\u201d","award":["22KJA330001"],"award-info":[{"award-number":["22KJA330001"]}]},{"name":"Young and Middle-aged Academic Leaders of \u201cBlue Project\u201d","award":["2022-29"],"award-info":[{"award-number":["2022-29"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>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\u2013RIPK3\u2013MLKL 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\u2013RIPK3 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.<\/jats:p>","DOI":"10.3390\/toxics13090736","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T13:01:13Z","timestamp":1756818073000},"page":"736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Methamphetamine Exposure Induces Neuronal Programmed Necrosis by Permeabilizing Mitochondria via the RIPK1\u2013RIPK3\u2013MLKL Axis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4364-7131","authenticated-orcid":false,"given":"Peng","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"},{"name":"Departoment of Emergency Medicine, Affiliated Peple\u2019s Hospital of Jiangsu University, Zhenjiang 212002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiankang","family":"Xuan","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixiao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"An","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sining","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoyang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Hygienic Analysis and Detection, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqingyang","family":"Hui","sequence":"additional","affiliation":[{"name":"The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Cheng","sequence":"additional","affiliation":[{"name":"Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Xiong","sequence":"additional","affiliation":[{"name":"Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"The Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xufeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.pbb.2019.02.008","article-title":"Enrichment-induced differences in methamphetamine drug discrimination in male rats","volume":"179","author":"Chacho","year":"2019","journal-title":"Pharmacol. 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