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

Article

Author: Wu, Cui-Cui ; Tian, Xue-Bi ; Ge, Meng-Meng ; Zhang, Guang-Xiong ; Zhang, Wen ; Yuan, Xiao-Man ; Gao, Feng ; Zhao, Feng-Tian ; Han, Si-Yi ; Zhang, Xiao-Yu ; Tian, Yu-Ke

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.

01 Oct 2024·Cytokine

COX-2 optimizes cardiac mitochondrial biogenesis and exerts a cardioprotective effect during sepsis

Article

Author: Tang, Yuting ; Luo, Zhengyang ; Yuan, Ludong ; Huang, Lingjin ; Liang, Pengfei ; Lin, Xiaofang ; Wang, Shuxin ; Jiang, Bimei ; Yin, Leijing

BACKGROUNDSeptic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E₂ (PGE₂), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function.OBJECTIVEThis study aims to demonstrate that COX-2/PGE₂ can protect against septic cardiomyopathy by regulating mitochondrial function.METHODSCecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection.RESULTSThe experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE₂ could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE₂ on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE₂ on the heart was also verified in the septic mice.CONCLUSIONCollectively, these results suggested that COX-2/PGE₂ pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE₂ only acted as an inflammatory factor.

01 Sep 2024·Shock

MECHANISM OF MICRORNA-218-5P IN MITOCHONDRIAL BIOGENESIS OF SEPSIS-INDUCED ACUTE KIDNEY INJURY BY THE REGULATION OF PGC-1Α

Article

Author: Hu, Shuli ; Fang, Jun ; Fan, Xuepeng ; Yang, Xiuhong ; Kuang, Jing

ABSTRACTBackground: Sepsis-induced acute kidney injury (SI-AKI) is a kind of kidney dysfunction, which brings a lot of suffering. This study aimed to figure out the role of the miR-218-5p/PGC-1α axis in SI-AKI. Methods: AKI mouse model was established through cecal ligation and puncture. PGC-1α expression was activated using an activator ZLN005 before the serum and tissue samples were collected. Next, pathological structure and apoptosis of kidney tissues were observed. Levels of blood urea nitrogen, serum creatinine, and indicators of inflammation and oxidative stress were assessed. Moreover, reactive oxygen species and mitochondrial membrane potential levels, adenosine 5′-triphosphate content, and mitochondrial ultrastructure of kidney tissues were observed. HK2 cells were treated by lipopolysaccharide (LPS) to mimic sepsis in vitro, followed by evaluation of cell survival and apoptosis, inflammation, and oxidative stress. Subsequently, the binding relation between PGC-1α and miR-218-5p was predicted and validated. Then expression of PGC-1α and miR-218-5p was detected. PGC-1α and miR-218-5p expression were intervened to detect their influences in mitochondrial biogenesis. At last, miR-218-5p was overexpressed in ZLN005 (PGC-1α activating agent) pretreated SI-AKI mice to validate the mechanism. Results: PGC-1α is poorly expressed in SI-AKI, but overexpression of PGC-1α using ZLN005 alleviated SI-AKI injury and promoted mitochondrial biogenesis in AKI mice, and relieved LPS-induced cell injury. PGC-1α is a target of miR-218-5p. Downregulation of miR-218-5p expression in HK2 cells attenuated mitochondrial biogenesis disorder. Inhibition of PGC-1α annulled the role of miR-218-5p silencing in cells. In vivo, miR-218-5p overexpression partly reversed the protective role of ZLN005 in SI-AKI mice. Conclusion: miR-218-5p targeted PGC-1α to disrupt mitochondrial biogenesis, thereby exacerbating SI-AKI.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Preclinical	CN	Shanghai Institute of Materia Medica Chinese Academy of Sci	14 Mar 2013

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