Postoperative cognitive dysfunction (POCD) is a prevalent clinical issue following anesthesia and surgery. The onset of POCD, which is closely linked to circadian rhythm disturbance in previous studies, yet the underlying mechanism remains elusive. There is increasing evidence showed that mitochondrial architecture is coordinated by the circadian clock which DRP1 playing a crucial role. Nonetheless, how DRP1's mediation of mitochondrial dynamics influences POCD through circadian rhythm disruption is still unclear. To investigate this, mice were subjected to 6 h of 1.5 % isoflurane anesthesia from Zeitgeber Time ZT 14 to ZT20 to induce POCD. HT-22 cells underwent prolonged exposure to isoflurane in vitro. Cognitive function was assessed using the Y-maze and fear conditioning tests. Q-PCR and Western blot analyses were performed to measure relative protein expression. Mice's gross movement rhythms were continuously monitored using Mini-Mitter. Mitochondrial morphology was examined via Mito-Tracker imaging. ATP and ROS level were measured to evaluate mitochondrial function. Isoflurane anesthesia compromised the clock control of DRP1 activity in the hippocampus. This disruption of DRP1 phosphorylation rhythm impaired circadian ATP production, affected mitochondrial morphology and function, exacerbated circadian rhythm disturbances, and ultimately led to cognitive deficits in mice. Pretreatment with Mdivi-1, a specific DRP1 inhibitor, managed to reconstruct mitochondrial morphology and function, restore circadian ATP production and rhythm, thereby alleviating the cognitive impairment induced by isoflurane anesthesia. This study suggests that circadian DRP1 activity's regulation of mitochondrial energy metabolism in the hippocampus may play a significant role in the pathogenesis of POCD in mice.

01 Feb 2025·Life Sciences

G6PD protects against cerebral ischemia-reperfusion injury by inhibiting excessive mitophagy

Article

Author: Li, Yilin ; Yu, Guixiang ; Zhu, Hua ; Gao, Yikun ; Ye, Yingze ; Chen, Lei ; Li, Yina ; Gu, Lijuan ; Wang, Jin

AIMSCerebral ischemia-reperfusion injury (CIRI) exacerbates post-stroke brain damage. We aimed to understand the role of glucose-6-phosphate dehydrogenase (G6PD) in CIRI and mitophagy.MATERIALS AND METHODSLentivirus and small interfering RNA were utilized to suppress G6PD in tissues and cells, leading to the establishment of in vivo and in vitro models of ischemia-reperfusion following middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/ reoxygenation (OGD/R). The expression and function of G6PD were investigated through differential gene analysis and weighted correlation network analysis (WGCNA), immunofluorescence, and western blotting (WB).KEY FINDINGSG6PD mRNA levels increased 3 d after MCAO, and G6PD protein expression was elevated in the ischemic penumbra of mice and HT22 cells following OGD/R. G6PD knockdown increased neural deficits, enlarged infarct volume in mice after CIRI, and reduced HT22 cell survival during OGD/R. WGCNA indicated a correlation between G6PD and mitophagy in CIRI. Following G6PD knockdown, the p-DRP1/DRP ratio increased, the PINK1/Parkin pathway was further activated, and TOMM20 expression was downregulated. The mitophagy inhibitor Mdivi-1 reversed these changes, as well as the nerve damage caused by G6PD knockdown, and alleviated mitochondrial damage in the ischemic penumbra.SIGNIFICANCEThe role of G6PD in CIRI was revealed and its interaction with mitophagy was explored, providing important insights for understanding the molecular mechanism of CIRI and developing new therapeutic strategies.

01 Feb 2025·Phytomedicine

4-hydroxybenzoic acid induces browning of white adipose tissue through the AMPK-DRP1 pathway in HFD-induced obese mice

Article

Author: Kim, Sang Hee ; Ahn, Kwang Seok ; Park, Ja Yeon ; Jung, Se Jin ; Park, Woo Yong ; Song, Gahee ; Um, Jae-Young

BACKGROUNDBeige adipocytes have physiological functions similar to brown adipocytes, which are available to increase energy expenditure through uncoupling protein 1 (UCP1) within mitochondria. Recently, many studies showed white adipocytes can undergo remodeling into beige adipocytes, called "browning", by increasing fusion and fission events referred to as mitochondrial dynamics.PURPOSEIn this study, we aimed to investigate the browning effects of 4-hydroxybenzoic acid (4-HA), one of the major compounds of black raspberries.METHODSWe examined the mechanism underlying the browning properties of 4-HA focusing on UCP1-dependent non-shivering thermogenesis in 3T3-L1 white adipocytes, high-fat diet (HFD)-induced obese male C57BL/6J mice, and cold-exposed male C57BL/6J mice.RESULTS4-HA treatment elevates browning markers such as UCP1, T-Box transcription factor 1, and PR domain containing 16, mitochondrial function factors like oxidative phosphorylation complex as well as mitochondrial dynamic-related factors like phosphorylated dynamin-related protein 1 (p-DRP1), DRP1, and mitofusin 1 in 3T3-L1 white adipocytes, which were also confirmed in inguinal white adipose tissue (iWAT) of HFD-induced obese mice. Mdivi-1 blocked the increased DRP1-mediated mitochondrial fission by 4-HA, and even the browning effect of 4-HA was abolished. Furthermore, 4-HA increased AMP-activated protein kinase (AMPK) in both the 3T3-L1 white adipocytes and iWAT of HFD-induced obese mice. Inhibition of AMPK with Compound C also blocked the 4-HA-induced mitochondrial fission and browning effect.CONCLUSIONS4-HA induces the browning of white adipocytes into beige adipocytes by regulating the DRP1-mediated mitochondrial dynamics through AMPK. These findings suggest that 4-HA could serve as a therapeutic candidate for obesity and related metabolic disorders.

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Indication	Highest Phase	Country/Location	Organization	Date
Perioperative ischaemia	Preclinical	US	University of Louisville	-
Reperfusion Injury	Preclinical	US	University of Louisville	-

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