Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 1:260:110119.
doi: 10.1016/j.neuropharm.2024.110119. Epub 2024 Aug 27.

The PGC-1α/ERRα/ULK1 pathway contributes to Perioperative neurocognitive disorders by inducing mitochondrial dysfunction and activating NLRP3 inflammasome in aged mice

Wen Zhang  1 , Cui-Cui Wu  1 , Meng-Meng Ge  1 , Xiao-Man Yuan  1 , Si-Yi Han  1 , Feng-Tian Zhao  1 , Xiao-Yu Zhang  1 , Feng Gao  1 , Yu-Ke Tian  1 , Guang-Xiong Zhang  2 , Xue-Bi Tian  3
Affiliations

The PGC-1α/ERRα/ULK1 pathway contributes to Perioperative neurocognitive disorders by inducing mitochondrial dysfunction and activating NLRP3 inflammasome in aged mice

Wen Zhang et al. Neuropharmacology. .

Abstract

Perioperative neurocognitive disorders (PND) are intractable, indistinct, and considerably diminish the postoperative quality of life of patients. It has been proved that Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was involved in neurodegenerative diseases by regulating mitochondrial biogenesis. The underlying mechanisms of PGC-1α and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in PND are not well understood. In this study, we constructed a model of laparotomy in aged mice, and then examined the cognition changes with novel object recognition tests and fear condition tests. The protein levels of PGC-1α and NLRP3 in the hippocampus were detect after surgery. Our results showed that NLRP3 and downstream PI3K/AKT pathway expressions were augmented in the hippocampus after surgery, whereas, the expressions of PGC-1α/estrogen-related receptor α (ERRα)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway were diminished after surgery. In addition, we found that NLRP3 was mainly co-localized with neurons in the hippocampus, and synaptic-related proteins were reduced after surgery. At the same time, transmission electron microscopy (TEM) showed that mitochondria were impaired after surgery. Pharmacological treatment of MCC950, a selective NLRP3 inhibitor, effectively alleviated PND. Activation of PGC-1α with ZLN005 significantly ameliorated PND by enhancing the PGC-1α/ERRα/ULK1 signaling pathway, and further suppressing NLRP3 activation. As a result, we conclude that suppression of the PGC-1α/ERRα/ULK1 signaling pathway is the primary mechanism of PND which caused mitochondrial dysfunction, and activated NLRP3 inflammasome and downstream PI3K/AKT pathway, eventually improved cognitive dysfunction.

Keywords: Mitochondrial dysfunction; NLRP3 inflammasome; PGC-1α/ERRα/ULK1; PI3K/AKT pathway; Perioperative neurocognitive disorders.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xuebi Tian and Wen Zhang reports financial support was provided by the National Natural Science Foundation of China. Xuebi Tian and Wen Zhang reports a relationship with Huazhong University of Science and Technology Tongji Medical CollegeTongji Hospital that includes: non-financial support. Xuebi Tian and Wen Zhang has patent None pending to None. Zhang Wen and Wu Cuicui carried out the model building, performed the Western blot, coordinated the lab's work, and drafted the manuscript. Ge Mengmeng took care of the Immunofluorescence and drafted the manuscript. Yuan Xiaoman, Han Siyi, and Zhao Fengtian carried out the NORT and FCT tests and drafted the manuscript. Zhang Xiaoyu carried out the Western blot and drafted the manuscript. Gao Feng, Tian Yuke, Zhang Guangxiong and Tian Xuebi performed the statistical analysis and drafted the manuscript. All authors read and approved the final manuscript. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Similar articles

See all similar articles

Cited by

MeSH terms

Substances

LinkOut - more resources