SIRT4 Expression Ameliorates the Detrimental Effect of Heat Stress via AMPK/mTOR Signaling Pathway in BMECs

Ding, Qiang; Wang, Yue; Xia, Shu-Wen; Zhao, Fang; Zhong, Jun; Wang, Huili; Chen, Kun-Lin

doi:10.3390/ijms232113307

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…Furthermore, Sirt4 exhibited a safeguarding role in vascular endothelial cells, shielding them from injury induced by oxidized low-density lipoprotein 57 . Ding et al's work in bovine mammary epithelial cells showed that SIRT4 depletion resulted in heightened ROS generation 58 . Our study aligns with these findings, demonstrating that Sirt4 knockdown in chondrocytes increased ROS production, while Sirt4 overexpression countered TBHP-induced ROS levels.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction

Lin,

Wu,

et al. 2024

Int. J. Biol. Sci.

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Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of osteoarthritis (OA). Nevertheless, the precise molecular mechanisms underlying chondrocyte senescence remain poorly understood. To address this knowledge gap, we conducted an investigation into the involvement of Sirtuin 4 (Sirt4) in chondrocyte senescence. Our experimental findings revealed a downregulation of Sirt4 expression in TBHP-induced senescent chondrocytes in vitro, as well as in mouse OA cartilage. Additionally, we observed that the knockdown of Sirt4 in chondrocytes promoted cellular senescence and cartilage degradation, while the overexpression of Sirt4 protected the cells against TBHP-mediated senescence of chondrocytes and cartilage degradation. Moreover, our findings revealed elevated levels of reactive oxygen species (ROS), abnormal mitochondrial morphology, compromised mitochondrial membrane potential, and reduced ATP production in Sirt4 knockdown chondrocytes, indicative of mitochondrial dysfunction. Conversely, Sirt4 overexpression successfully mitigated TBHP-induced mitochondrial dysfunction. Further analysis revealed that Sirt4 downregulation impaired the cellular capacity to eliminate damaged mitochondria by inhibiting Pink1 in chondrocytes, thereby enhancing the accumulation of ROS and facilitating chondrocyte senescence. Notably, the overexpression of Pink1 counteracted the effects of Sirt4 knockdown on mitochondrial dysfunction. Importantly, our study demonstrated the promise of gene therapy employing a lentiviral vector encoding mouse Sirt4, as it successfully preserved the integrity of articular cartilage in mouse models of OA. In conclusion, our findings provide compelling evidence that the overexpression of Sirt4 enhances mitophagy, restores mitochondrial function, and protects against chondrocyte senescence, thereby offering a novel therapeutic target and potential strategy for the treatment of OA.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction

Lin,

Wu,

et al. 2024

Int. J. Biol. Sci.

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“…Sirt4 blocks glutamine catabolism [ 70 ], which is required for the execution of ferroptosis [ 71 , 72 ]. Sirt4 is also considered to be the key regulator in the antioxidative defense system, and depletion of Sirt4 can induce the accumulation of ROS by decreasing the activity of antioxidant enzymes in bovine mammary epithelial cells [ 73 ]. These findings indicate the potential correlation between ferroptosis and Sirt4.…”

Section: Discussionmentioning

confidence: 99%

AGER1 deficiency-triggered ferroptosis drives fibrosis progression in nonalcoholic steatohepatitis with type 2 diabetes mellitus

Gong,

Liu,

Zhang

et al. 2023

Cell Death Discov.

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Hyperglycemia is an independent risk factor for the rapid progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis with an incompletely defined mechanism. Ferroptosis is a novel form of programmed cell death that has been identified as a pathogenic mechanism in various diseases. However, the role of ferroptosis in the development of liver fibrosis in NASH with type 2 diabetes mellitus (T2DM) is unclear. Here, we observed the histopathological features of the progression of NASH to liver fibrosis as well as hepatocyte epithelial-mesenchymal transition (EMT) in a mouse model of NASH with T2DM and high-glucose-cultured steatotic human normal liver (LO2) cells. The distinctive features of ferroptosis, including iron overload, decreased antioxidant capacity, the accumulation of reactive oxygen species, and elevated lipid peroxidation products, were confirmed in vivo and in vitro. Liver fibrosis and hepatocyte EMT were markedly alleviated after treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, a decrease in the gene and protein levels of AGE receptor 1 (AGER1) was detected in the transition from NASH to liver fibrosis. Overexpression of AGER1 dramatically reversed hepatocyte EMT in high-glucose-cultured steatotic LO2 cells, whereas the knockdown of AGER1 had the opposite effect. The mechanisms underlying the phenotype appear to be associated with the inhibitory effects of AGER1 on ferroptosis, which is dependent on the regulation of sirtuin 4. Finally, in vivo adeno-associated virus-mediated AGER1 overexpression effectively relieved liver fibrosis in a murine model. Collectively, these findings suggest that ferroptosis participates in the pathogenesis of liver fibrosis in NASH with T2DM by promoting hepatocyte EMT. AGER1 could reverse hepatocyte EMT to ameliorate liver fibrosis by inhibiting ferroptosis. The results also suggest that AGER1 may be a potential therapeutic target for the treatment of liver fibrosis in patients with NASH with T2DM.

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“…In another study, Shi et al reported that the overexpression of SIRT4 reduced inflammation and the production of ROS [ 43 ]. SIRT4 has also been shown to reduce the oxidative stress caused by heat stress by improving mitochondrial function [ 44 ]. Collectively, these results indicate that SIRT4 has significant potential for regulating inflammation and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin4 alleviates severe acute pancreatitis by regulating HIF-1α/HO-1 mediated ferroptosis

Liu,

Cui,

Mei

et al. 2023

Cell Death Dis

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Acute pancreatitis (AP) is a common emergency of the digestive system and serious cases can develop into severe acute pancreatitis (SAP), which ortality rates up to 30%. Sirtuin4 (SIRT4) is a member of the sirtuin family, and plays a key role in inflammation and oxidative stress. However, the potential role of SIRT4 in SAP has yet to be elucidated. In the present study, we found that the expression level of SIRT4 in human AP was downregulated by screening a public database, suggesting that SIRT4 may play a role in AP. Subsequently, we used L-arginine (L-Arg) to induce SAP in SIRT4 knockout (SIRT4_KO) and SIRT4 overexpression (AAV_SIRT4) mice. The results showed that the pancreatic tissue injury and related lung and kidney injury were serious in SIRT4_KO mice after SAP induction, but were significantly reduced in AAV_SIRT4 mice. More importantly, we found that the levels of antioxidant factors GSH and SOD were decreased in SIRT4_KO mice, and the production of oxidative products and lipid peroxidation markers was increased, suggesting that SIRT4 was involved in inflammation and oxidative stress during SAP. Further studies showed that the absence or overexpression of SIRT4 affected the expression level of Hypoxia-inducible factor-1α (HIF-1α) after SAP induction, and regulated the expression of ferroptosis related proteins by mediating HIF-1α/HO-1 pathway. Collectively, our study revealed that SIRT4 plays a protective role in SAP by regulating the HIF-1α/HO-1 pathway to inhibit ferroptosis.

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SIRT4 Expression Ameliorates the Detrimental Effect of Heat Stress via AMPK/mTOR Signaling Pathway in BMECs

Cited by 9 publications

References 49 publications

Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction

Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction

AGER1 deficiency-triggered ferroptosis drives fibrosis progression in nonalcoholic steatohepatitis with type 2 diabetes mellitus

Sirtuin4 alleviates severe acute pancreatitis by regulating HIF-1α/HO-1 mediated ferroptosis

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