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However, increasing scientific attention has been directed toward its neurotoxicity. Diester-diterpenoid alkaloids (DDAs), such as aconitine (AC), mesaconitine (MA), and hypaconitine (HA), have been identified as the principal toxic constituents of Aconitum. Although disruption of calcium homeostasis has been demonstrated to mediate DDAs-induced neurotoxicity, the key neurotoxic components and their underlying molecular mechanisms remain unclear. Our study employed both in vivo and in vitro to compare the neurotoxic effects of structurally similar DDAs (AC, MA, and HA) to screen for the key effector substance for further investigation. Experiments conducted in both zebrafish and SH-SY5Y cells revealed that AC exerted more significant regulatory effects on mitophagy, calcium homeostasis, and two-pore channels (TPCs) than MA and HA. Consequently, subsequent mechanistic studies focused on the role of the TPCs\u2013Ca2+\u2013mitophagy axis in AC-induced neurotoxicity. Treatment with the TPCs inhibitor Ned-19 suppressed mitochondrial\u2013lysosomal fusion and reversed the AC-induced upregulation of LC3B-II\/I and Parkin, thereby attenuating the overactivation of mitophagy markers in SH-SY5Y cells. Similarly, the calcium chelator BAPTA-AM diminished mitochondrial\u2013lysosomal colocalization and LC3B-II\/I protein levels. In summary, AC disrupts lysosomal TPCs-mediated calcium homeostasis, leading to excessive mitophagy more pronounced than that of MA and HA. These findings not only deepen our understanding of the intrinsic mechanisms underlying AC-induced neurotoxicity, but also provide new experimental evidence supporting the identification of AC as the primary neurotoxic component in the genus Aconitum L.<\/jats:p>","DOI":"10.1093\/toxres\/tfag008","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T12:10:49Z","timestamp":1769515849000},"source":"Crossref","is-referenced-by-count":2,"title":["Aconitine outperforms mesaconitine and hypaconitine in triggering excessive mitophagy via lysosomal two-pore channels disruption in SH-SY5Y cells and zebrafish"],"prefix":"10.1093","volume":"15","author":[{"given":"Han","family":"Feng","sequence":"first","affiliation":[{"name":"School of Pharmacy and Key Laboratory of Standardization of Chinese Medicine, Ministry of Education, Chengdu University of Traditional Chinese Medicine , No. 1166, Liutai Avenue, Wenjiang District, Chengdu, 610075, Sichuan 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1166, Liutai Avenue, Wenjiang District, Chengdu, 610075, Sichuan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Key Laboratory of Standardization of Chinese Medicine, Ministry of Education, Chengdu University of Traditional Chinese Medicine , No. 1166, Liutai Avenue, Wenjiang District, Chengdu, 610075, Sichuan ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University , No. 17, Section 3, Renmin Nan Road, Wuhou District, Chengdu, 610041, Sichuan 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