Drp1-associated mitochondrial dysfunction and mitochondrial autophagy: a novel mechanism in triptolide-induced hepatotoxicity

Hasnat, Muhammad; Yuan, Ziqiao; Naveed, Muhammad; Khan, Asifullah; Raza, Faisal; Xu, Dengqiu; Ullah, Aftab; Sun, Linxin; Zhang, Luyong; Jiang, Zhenzhou

doi:10.1007/s10565-018-9447-8

Cited by 80 publications

(47 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The gene expression and protein activation of MSP in liver biopsies from 55 patients with severe ALD demonstrated that the mitochondrial fragmentation pathway was hyperactivated, and among all the MSP, Drp1 was found consistently overexpressed in patients affected by AH. Other studies have shown important effects on mitochondrial dynamics and on Drp1 during liver injury, but these observations are limited to in vitro or animal models (Hasnat et al, ; Li et al, ; Ramachandran et al, ; Yang et al, ). A lack of confirmation of experimental results in more relevant models (whole human tissue) and especially in patients hinders the translation of knowledge clinically and is mainly due to the difficulty in obtaining such samples.…”

Section: Discussionmentioning

confidence: 99%

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease

Palma

Riva

Moreno

et al. 2020

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown.Methods: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM).Results: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model.Conclusions: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.

show abstract

Section: Discussionmentioning

confidence: 99%

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease

Palma

Riva

Moreno

et al. 2020

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…These results suggest that TP inhibits cell proliferation and induces apoptosis via the Fas death pathway and the mitochondrial pathway. An increased expression of the Drp1 fission protein in vitro and in vivo suggested that the mitochondrial dysfunction and mitochondrial autophagy signaling pathway might be the mechanism of TP‐induced hepatotoxicity (Hasnat et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…An increased expression of the Drp1 fission protein in vitro and in vivo suggested that the mitochondrial dysfunction and mitochondrial autophagy signaling pathway might be the mechanism of TPinduced hepatotoxicity (Hasnat et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Triptolide‐induced hepatotoxicity via apoptosis and autophagy in zebrafish

Huo

Zhang

et al. 2019

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

Previous research about the development of triptolide (TP) as a natural active compound has often focused on hepatotoxicity. Among its various mechanisms, autophagy and apoptosis are two important signaling pathways. In this study, we used zebrafish to establish a TP‐induced hepatotoxicity model, and investigated the roles of autophagy and apoptosis in the progress of liver injury. Zebrafish exposed to TP showed increased mortality and malformation because of the increased drug dose and duration of exposure. Meanwhile, we found that TP induced liver injury in a time‐ and dose‐dependent manner, which was observed as a reduction in liver area, slow yolk absorption, upregulation of transaminase and local neurosis. With the application of the high‐content imaging system (HCIS) technique in liver 3D imaging in vivo, clear imaging of the zebrafish liver was achieved. The results showed a decrease in volume and location of necrosis in the liver after TP exposure. Increased expression of inflammatory cytokines genes tumor necrosis factor (Tnf)α, Il1β and Il6 were shown, particularly Tnfα. The Fas‐Caspase8 signaling pathway was activated. The apoptosis‐related gene Bcl‐2 was increased, and Bax, Caspase9 and Caspase3 were increased. However, autophagy related genes Beclin1, Atg5, Atg3 and Lc3 were increased more significantly, and the changes of Beclin1 and Atg5 were the most severe. This study successfully established a TP‐induced zebrafish hepatotoxicity model and applied the HCIS technique in a zebrafish hepatotoxicity study. The result indicated Fas might be the main target of TP‐induced hepatotoxicity. Autophagy played a more important role than apoptosis and was characterized by the overexpression of Beclin1 and Atg5.

show abstract

“…Obviously, the lack of DRP1 similar to the inhibition of autophagy contributed to the cell's sensitivity to both chemo-and radio-resistance. [32,49,50] In spite of this study couldn't explain clearly the played role of DRP1 in the autophagy process, while revealing evidence of light is likely to the DRP1 participated with mitochondrial DNA stability ( Figure. 4e) [51,52].…”

Section: Discussionmentioning

confidence: 99%

Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

Cheng

Chow

Chiao

et al. 2019

Preprint

View full text Add to dashboard Cite

172 words Cheng, 2 -Text: 16 pages, 3732 words Figures, 5 Tables, 1 Cheng, 3 - Translational RelevanceThis study shows that dynamin-related protein 1 (DRP1), an essential 80-kDa GTPase, which is involved in mitochondrial fission, and mitochondrial protein imports, is highly expressed in glioblastoma multiforme (GBM). Moreover, we demonstrate that DRP1 expression is closely associated with radiation sensitivity, cancer progression, and patients' cumulative survival. In vitro, inhibition of DRP1 expression reduced the nuclear entry of DNA repair-associated enzymes, such as ATM, but increased radiation sensitivity and nuclear drug uptakes of glioblastoma cells. More importantly, the silencing of DRP1 induced cellular autophagy. These results indicate that DRP1 overexpression could be a prospective radio-resistant phenotype in GBM and a clinically important target for improving the effectiveness of radiation therapy. AbstractBackground: Dynamin-related protein 1 (DRP1) is a GTPase involved in mitochondrial fission, mitochondrial protein imports, and drug sensitivity, suggesting an association with cancer progression. This study is to evaluate the prognostic significance of DRP1 in glioblastoma multiforme (GBM). Material and Methods: DRP1 expression was measured by immunohistochemistry and Western blotting. Correlations between DRP1 expression and clinicopathological parameters were analyzed by statistical analysis. Differences in survival were compared by a log-rank test.Results: DRP1 expression was detected in 87.2% (41/47) patients with GBM. Patients with higher DRP1 levels had worse survival (p = 0.0398). In vitro, silencing of DRP1 reduced cell proliferation, metastatic potential, and radiation resistance. The addition of shikonin inhibited DRP1 expression and increased drug uptake. Moreover, shikonin reduced the nuclear entry of DNA repair-associated enzymes and increased radiation sensitivity, suggesting that to reduce DRP1 expression could inhibit DNA repair and increase the radiation sensitivity of GBM cells. Conclusion:Our results indicate that DRP1 overexpression is a prospective radio-resistant phenotype in GBM. Therefore, DRP1 could be a potential target for improving the effectiveness of radiation therapy.

show abstract

Drp1-associated mitochondrial dysfunction and mitochondrial autophagy: a novel mechanism in triptolide-induced hepatotoxicity

Cited by 80 publications

References 40 publications

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease

Triptolide‐induced hepatotoxicity via apoptosis and autophagy in zebrafish

Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

Contact Info

Product

Resources

About