SIRT3 protects kidneys from ischemia-reperfusion injury by modulating the DRP1 pathway to induce mitochondrial autophagy

Zhao, Wen‐Yu; Sui, Mingxing; Chen, Rui; Lu, Heng; Zhu, Youhua; Zhang, Lei; Zeng, Li

doi:10.1016/j.lfs.2021.120005

Cited by 27 publications

(18 citation statements)

References 33 publications

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“…Additionally, it had been reported that the expression of SIRT3 was related to cellular autophagy. Upregulating SIRT3 contributed to inducing mitochondrial autophagy processes 21 . SIRT3 might be the essential factor for mediating the effect of Trehalose on osteoblast autophagy.…”

Section: Introductionmentioning

confidence: 94%

RETRACTED: Trehalose improves palmitic acid‐induced apoptosis of osteoblasts by regulating SIRT3‐medicated autophagy via the AMPK/mTOR/ULK1 pathway

et al. 2022

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Accumulation of lipid substances decreased the activity of osteoblasts. Trehalose is a typical stress metabolite to form a protective membrane on cell surface which has been demonstrated to regulate lipid metabolism. This activity of Trehalose indicates the potential effect of osteoporosis treatment. Our study aimed to determine the therapeutic effect of Trehalose in high fat-induced osteoporosis. We used palmitic acid (PA) to mimic the state of high fat and observed the apoptosis ratio of osteoblasts increased. After adding Trehalose, the apoptosis ratio decreased obviously. Autophagy is a regulatory means involved in the process of apoptosis.We detected the autophagy protein and found that the expression of Beclin-1, Atg5, and LC3 II increased, and p62 decreased after Trehalose treatment. When adding an autophagy inhibitor (3-MA), the expression of Beclin-1, Atg5, and LC3 II decreased, and p62 increased. These results indicated autophagy was an important factor involved in the preventive effect of Trehalose in PA-induced apoptosis. SIRT3 is a mitochondrial gene that can inhibit apoptosis, which has been reported to promote autophagy. We used SIRT3-siRNA to silence the expression of SIRT3 and found the effect of Trehalose was counteracted. The apoptosis ratio increased and the expression of Beclin-1, Atg5, and LC3 II decreased, p62 increased. Additionally, we also fed the mice with a high-fat diet (HFD) and intragastrical Trehalose. The results showed that Trehalose could inhibit the bone mass loss with HFD. Our study revealed the effect and mechanism of Trehalose in the treatment of osteoporosis.

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Section: Introductionmentioning

confidence: 94%

RETRACTED: Trehalose improves palmitic acid‐induced apoptosis of osteoblasts by regulating SIRT3‐medicated autophagy via the AMPK/mTOR/ULK1 pathway

et al. 2022

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“…To further explain the effects of RCAN1 on HR injury, we focused on mitochondrial fission. Drp1-related mitochondrial fission is noted as a critical step in aggravating HR injury [ 15 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulator of calcineurin 1 deletion attenuates mitochondrial dysfunction and apoptosis in acute kidney injury through JNK/Mff signaling pathway

Xiao

Liu

et al. 2022

Cell Death Dis

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Ischemia-reperfusion (I/R) induced acute kidney injury (AKI), characterized by excessive mitochondrial damage and cell apoptosis, remains a clinical challenge. Recent studies suggest that regulator of calcineurin 1 (RCAN1) regulates mitochondrial function in different cell types, but the underlying mechanisms require further investigation. Herein, we aim to explore whether RCAN1 involves in mitochondrial dysfunction in AKI and the exact mechanism. In present study, AKI was induced by I/R and cisplatin in RCAN1flox/flox mice and mice with renal tubular epithelial cells (TECs)-specific deletion of RCAN1. The role of RCAN1 in hypoxia-reoxygenation (HR) and cisplatin-induced injury in human renal proximal tubule epithelial cell line HK-2 was also examined by overexpression and knockdown of RCAN1. Mitochondrial function was assessed by transmission electron microscopy, JC-1 staining, MitoSOX staining, ATP production, mitochondrial fission and mitophagy. Apoptosis was detected by TUNEL assay, Annexin V-FITC staining and Western blotting analysis of apoptosis-related proteins. It was found that protein expression of RCAN1 was markedly upregulated in I/R- or cisplatin-induced AKI mouse models, as well as in HR models in HK-2 cells. RCAN1 deficiency significantly reduced kidney damage, mitochondrial dysfunction, and cell apoptosis, whereas RCAN1 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration demonstrated that RCAN1 increases the phosphorylation of mitochondrial fission factor (Mff) by binding to downstream c-Jun N-terminal kinase (JNK), then promotes dynamin related protein 1 (Drp1) migration to mitochondria, ultimately leads to excessive mitochondrial fission of renal TECs. In conclusion, our study suggests that RCAN1 could induce mitochondrial dysfunction and apoptosis by activating the downstream JNK/Mff signaling pathway. RCAN1 may be a potential therapeutic target for conferring protection against I/R- or cisplatin-AKI.

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“…Mitochondria's role in diseases is no longer limited to provide energy to cells, they also play a role in signaling, gene control, cellular calcium regulation, and activation of cell death pathways. Sirt3 influences mitochondrial intracellular function through the homeostatic regulation of mitochondrial fission 57 , biosynthesis 58 , and autophagy 59 , in addition to altering their metabolic activity. The results of this study predicted that patients with lower serum Sirt3 levels have a worse prognosis, and our survival analysis backed up this prediction.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Sirt3 serves as a biomarker for sepsis diagnosis and mortality prediction

Liu

Zhou

Chen

et al. 2022

Sci Rep

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The purpose of this study is to determine whether the levels of serum Sirt3 correlate with disease severity and perfusion indicators in septic patients, as well as to assess the clinical value of Sirt3 as a potential novel marker for sepsis diagnosis and mortality prediction. A total of 79 patients in the ICU were included in the study, of which 28 were postoperatively noninfectious and the remaining 51 patients were all diagnosed with sepsis during the study period. The levels of Sirt3 were detected and dynamically monitored by enzyme-linked adsorption method, Pearson or Spearman coefficient for correlation analysis between Sirt3 and clinical indicators, ROC curve for evaluation of diagnosis and mortality prediction, Kaplan–Meier method for the significance of Sirt3 in 28-day survival. The serum levels of Sirt3 were lower in the sepsis patients on day 1 (P < 0.0001), and the septic shock group had lower Sirt3 levels than the sepsis group (P = 0.013). Sirt3 had good negative correlations with SOFA scores both in sepsis and septic shock groups (Pearson: r2 = − 0.424, − 0.518; P = 0.011, 0.040), and Sirt3 correlated strongly with ScvO2 in the septic shock group (Pearson: r2 = − 0.679, P = 0.004) and with PCT in the sepsis group (Pearson: r2 = − 0.409, P = 0.015). Sirt3 not only performed well in identifying sepsis (AUC = 0.995, 95% CI 0.987–1, P < 0.0001) but also greatly enhanced lactate's specificity in detecting septic shock (from 91.43 to 94.29%). Patients in the low Sirt3 group had higher ScvO2, lactate, APACHE II score, SOFA score, longer ICU stays, and worse indicators of inflammation (TNF-α, IL-6) and infection (PCT) than those in the high Sirt3 group (P < 0.05). Additionally, Sirt3 can predict mortality of sepsis (AUC = 0.746, 95% CI 0.571–0.921, P = 0.022), patients with serum Sirt3 < 10.07 pg/ml have a lower 28-day survival (log-rank P = 0.008). Low serum levels of Sirt3 are significantly correlated with the disease severity. At the same time, Sirt3 increases the sensitivity of lactate to detect “cellular hypoxia” in septic shock. Sirt3 is a promising biomarker for the diagnosis of sepsis and predicting mortality risk in septic patients.

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SIRT3 protects kidneys from ischemia-reperfusion injury by modulating the DRP1 pathway to induce mitochondrial autophagy

Cited by 27 publications

References 33 publications

RETRACTED: Trehalose improves palmitic acid‐induced apoptosis of osteoblasts by regulating SIRT3‐medicated autophagy via the AMPK/mTOR/ULK1 pathway

RETRACTED: Trehalose improves palmitic acid‐induced apoptosis of osteoblasts by regulating SIRT3‐medicated autophagy via the AMPK/mTOR/ULK1 pathway

Regulator of calcineurin 1 deletion attenuates mitochondrial dysfunction and apoptosis in acute kidney injury through JNK/Mff signaling pathway

Mitochondrial Sirt3 serves as a biomarker for sepsis diagnosis and mortality prediction

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