PKCδ modulates SP1 mediated mitochondrial autophagy to exacerbate diacetylmorphine-induced ferroptosis in neurons.

Autor: Zhuang M; Xinjiang Medical University, School of Basic Medical Science, Urumqi 830017, China., Zhu S; Xinjiang Medical University, School of Basic Medical Science, Urumqi 830017, China., Su L; Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China., Liu L; Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China., Ji M; Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China., Dai C; Xinjiang Medical University, School of Basic Medical Science, Urumqi 830017, China., Liu J; Xinjiang Medical University, School of Basic Medical Science, Urumqi 830017, China., Zhang W; Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China. Electronic address: zwyhr100@163.com., Pu H; Xinjiang Medical University, School of Basic Medical Science, Urumqi 830017, China; Key Laboratory of Forensic Medicine, School of Basic Medical Sciences, Xinjiang Medical University, China; Department of Discipline Construction, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China. Electronic address: 576250630@qq.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Dec 25; Vol. 143 (Pt 2), pp. 113468. Date of Electronic Publication: 2024 Oct 26.
DOI: 10.1016/j.intimp.2024.113468
Abstrakt: Diacetylmorphine (DA) is widely implicated in neuronal injury; however, the underlying mechanisms remain unclear. We investigated the role of iron metamorphosis in DA-induced neurotoxicity using Sprague-Dawley rats and PC12 and SH-SY5Y cells. Tandem mass tag proteomics analysis showed that the upregulation of protein kinase C delta (PKCδ) and iron metabolism-related protein transferrin receptor (TFRC) significantly the enriched iron metabolism pathway. Subsequent experiments showed that DA exposure significantly upregulated PKCδ in PC12 cells, which increased the nuclear translocation of specificity protein 1 (SP1), and the intracellular free iron and lipid peroxide levels. In addition, silencing of PKCδ in rats improved behaviour and restored the expression level of glutathione peroxidase 4 (GPX4). In addition, DA exposure activated mitochondrial autophagy in PC12 cells, leading to a decrease in the mitochondrial membrane potential, accumulation of reactive oxygen species (ROS), elevation of LC3 (which plays a key role in autophagy), and a decrease in p62 expression. Following the inhibition of autophagy, the mitochondrial membrane potential and ROS were restored, as was the expression of voltage-dependent anion channel 1 (VDAC1) and GPX4. In conclusion, the present study suggests that PKCδ regulates SP1, further exacerbating DA-induced neuronal ferroptosis. Therefore, inhibition of PKCδ and mitochondrial autophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following DA exposure.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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