Calcium dysregulation contributes to mitochondrial dysfunction and hippocampal necroptosis in TDCPP-induced cognitive impairment.

Authors

Xiaoxiao Wang, Furong Zhang, Zhaoxiong Liu, Yalong Qiang, Yihan Ye, Ruifang Liu, Mingxue Song, Jianwei Lou, Fuyong Song

Published in

Experimental neurology. Pages 116105. Oct 30, 2026. Epub Oct 30, 2026.

Abstract

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a widely used organophosphorus flame retardant, has been increasingly associated with adverse neurological effects; however, the mechanisms linking TDCPP exposure to hippocampal injury and cognitive impairment remain incompletely understood. In this study, we investigated whether calcium dysregulation and mitochondrial dysfunction contribute to TDCPP-induced neuronal injury. Subchronic TDCPP exposure in mice caused significant cognitive deficits and hippocampal neuronal loss, accompanied by activation of RIPK1/RIPK3/MLKL-related necroptotic signaling. In SH-SY5Y cells, TDCPP induced marked mitochondrial dysfunction, as evidenced by decreased mitochondrial membrane potential, enhanced mitochondrial permeability transition pore opening, and excessive mitochondrial fragmentation. Mechanistically, TDCPP induced intracellular Ca²⁺ overload and increased the calpain/CDK5 pathway, resulting in enhanced Drp1 phosphorylation and mitochondrial fission. Pharmacological inhibition of TRPA1 with HC-030031 markedly attenuated TDCPP-induced Ca²⁺ overload, calpain/CDK5-Drp1 pathway activation, mitochondrial dysfunction, and necroptosis-related neuronal injury. Consistently, genetic knockdown of TRPA1 produced similar protective effects against TDCPP-induced Ca²⁺ dysregulation, mitochondrial dysfunction, and necroptosis-related signaling. In contrast, Mdivi-1 treatment reduced mitochondrial fragmentation and necroptotic injury but did not substantially affect upstream Ca²⁺ dysregulation. Additionally, TDCPP exposure was accompanied by cytosolic mtDNA accumulation and increased expression of cGAS-STING pathway components and ZBP1 in the hippocampus, suggesting the involvement of mitochondrial damage-associated innate immune responses. Collectively, these findings suggest that Ca²⁺ dysregulation contributes to Drp1-associated mitochondrial dysfunction and hippocampal necroptotic injury during TDCPP-induced cognitive impairment, providing new mechanistic insight into the molecular basis of hippocampal neuronal vulnerability.

PMID:
42962795
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.

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