scholarly journals [Retracted] Hypoxia‑induced mitochondrial translocation of DNM1L increases mitochondrial fission and triggers mPTP opening in HCC cells via activation of HK2

2021 ◽  
Vol 45 (6) ◽  
Author(s):  
Min Cai ◽  
Ping He ◽  
Dian-Liang Fang
Keyword(s):  
Mitochondrial Fission ◽  
Mitochondrial Translocation ◽  
Mptp Opening ◽  
Hcc Cells

scholarly journals Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Qiongxia Deng ◽  
Ruowei Wen ◽  
Sirui Liu ◽  
Xiaoqiu Chen ◽  
Shicong Song ◽  
...  
Keyword(s):  
High Glucose ◽  
Noncoding Rna ◽  
Diabetic Kidney Disease ◽  
Mitochondrial Fission ◽  
Diabetic Mice ◽  
Podocyte Injury ◽  
Mitochondrial Translocation ◽  
Maternally Expressed Gene 3

Abstract Excessive mitochondrial fission plays a key role in podocyte injury in diabetic kidney disease (DKD), and long noncoding RNAs (lncRNAs) are important in the development and progression of DKD. However, lncRNA regulation of mitochondrial fission in podocytes is poorly understood. Here, we studied lncRNA maternally expressed gene 3 (Meg3) in mitochondrial fission in vivo and in vitro using human podocytes and Meg3 podocyte-specific knockdown mice. Expression of lncRNA Meg3 in STZ-induced diabetic mice was higher, and correlated with the number of podocytes. Excessive mitochondrial fission of podocytes and renal histopathological and physiological parameters were improved in podocyte-specific Meg3 knockdown diabetic mice. Elongated mitochondria with attenuated podocyte damage, as well as mitochondrial translocation of dynamin-related protein 1 (Drp1), were decreased in Meg3 knockout podocytes. By contrast, increased fragmented mitochondria, podocyte injury, and Drp1 expression and phosphorylation were observed in lncRNA Meg3-overexpressing podocytes. Treatment with Mdivi1 significantly blunted more fragmented mitochondria and reduced podocyte injury in lncRNA Meg3-overexpressing podocytes. Finally, fragmented mitochondria and Drp1 mitochondrial translocation induced by high glucose were reduced following treatment with Mdivi1. Our data show that expression of Meg3 in podocytes in both human cells and diabetic mice was higher, which regulates mitochondrial fission and contributes to podocyte injury through increased Drp1 and its translocation to mitochondria.

scholarly journals Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis

Oncotarget ◽  
2014 ◽  
Vol 6 (3) ◽  
pp. 1834-1849 ◽  
Author(s):  
Guobing Li ◽  
Jing Zhou ◽  
Amit Budhraja ◽  
Xiaoye Hu ◽  
Yibiao Chen ◽  
...  
Keyword(s):  
Mitochondrial Fission ◽  
Mitochondrial Translocation

scholarly journals DRP1 Inhibition Rescues Mitochondrial Integrity and Excessive Apoptosis in CS-A Disease Cell Models

2021 ◽  
Vol 22 (13) ◽  
pp. 7123
Author(s):  
Barbara Pascucci ◽  
Francesca Spadaro ◽  
Donatella Pietraforte ◽  
Chiara De Nuccio ◽  
Sergio Visentin ◽  
...  
Keyword(s):  
Mitochondrial Fission ◽  
Cell Models ◽  
Mitochondrial Fragmentation ◽  
Mitochondrial Translocation ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Integrity ◽  
Group A ◽  
Neurodevelopmental Abnormalities ◽  
Sun Sensitivity ◽  
Disease Cell

Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients.

scholarly journals Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction

2020 ◽  
Vol 126 (4) ◽  
pp. 456-470 ◽  
Author(s):  
Qingxun Hu ◽  
Huiliang Zhang ◽  
Nicolás Gutiérrez Cortés ◽  
Dan Wu ◽  
Pei Wang ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Mitochondrial Fission ◽  
Myocardial Damage ◽  
Nicotinamide Adenine ◽  
Heart Hypertrophy ◽  
Voltage Dependent Anion Channel ◽  
Heart Dysfunction ◽  
Mitochondrial Translocation ◽  
The Impact

Rationale: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. Objective: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. Methods and Results: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. Conclusions: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

scholarly journals NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

2018 ◽  
Vol 48 (4) ◽  
pp. 1675-1693 ◽  
Author(s):  
Junqin Sheng ◽  
Hongyan Li ◽  
Qin Dai ◽  
Chang Lu ◽  
Min Xu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Western Blotting ◽  
Mitochondrial Dynamics ◽  
Therapeutic Option ◽  
Mitochondrial Fission ◽  
Mitochondrial Oxidative Stress ◽  
Atp Production ◽  
Metabolism Disorder ◽  
P53 Signaling ◽  
Mptp Opening

Background/Aims: Disrupted mitochondrial dynamics, including excessive mitochondrial fission and mitophagy arrest, has been identified as a pathogenic factor in diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation and mitophagy arrest in the setting of DN remains unknown. Methods: Wild-type (WT) mice and NR4A1 knockout (NR4A1-KO) mice were used to establish a DN model. Mitochondrial fission and mitophagy were evaluated by western blotting and immunofluorescence. Mitochondrial function was assessed by JC-1 staining, the mPTP opening assay, immunofluorescence and western blotting. Renal histopathology and morphometric analyses were conducted via H&E, Masson and PASM staining. Kidney function was evaluated via ELISA, western blotting and qPCR. Results: In the present study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was actually activated by a chronic hyperglycemic stimulus. Higher NR4A1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, increased NR4A1 expression activated p53, and the latter selectively stimulated mitochondrial fission and inhibited mitophagy by modulating Mff and Parkin transcription. Excessive Mff-related mitochondrial fission caused mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. In addition, defective Parkin-mediated mitophagy repressed cellular ATP production and failed to correct the uncontrolled mitochondrial fission. However, NR4A1 knockdown interrupted the Mff-related mitochondrial fission and recused Parkin-mediated mitophagy, reducing the hyperglycemia-mediated mitochondrial damage and thus improving renal function. Conclusion: Overall, we have shown that NR4A1 functions as a novel malefactor in diabetic renal damage and operates by synchronously enhancing Mff-related mitochondrial fission and repressing Parkin-mediated mitophagy. Thus, finding strategies to regulate the balance of the NR4A1-p53 signaling pathway and mitochondrial homeostasis may be a therapeutic option for treating diabetic nephropathy in clinical practice.

scholarly journals Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes

2011 ◽  
Vol 301 (5) ◽  
pp. H1924-H1931 ◽  
Author(s):  
Youngil Lee ◽  
Hwa-Youn Lee ◽  
Rita A. Hanna ◽  
Åsa B. Gustafsson
Keyword(s):  
Cardiac Myocytes ◽  
Ubiquitin Ligase ◽  
Mitochondrial Fission ◽  
Dominant Negative ◽  
Protective Response ◽  
Interacting Protein ◽  
Potent Inducer ◽  
Mitochondrial Translocation ◽  
Adenovirus E1b ◽  
Mitofusin 1

The Bcl2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) is an atypical BH3-only protein that is associated with mitochondrial dysfunction and cell death. Bnip3 is also a potent inducer of mitochondrial autophagy, and in this study we have investigated the mechanisms by which Bnip3 induces autophagy in cardiac myocytes. We found that Bnip3 induced mitochondrial translocation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission in adult myocytes. Drp1-mediated mitochondrial fission correlated with increased autophagy, and inhibition of Drp1 reduced Bnip3-mediated autophagy. Overexpression of Drp1K38E, a dominant negative of Drp1, or mitofusin 1 prevented mitochondrial fission and autophagy by Bnip3. Also, inhibition of mitochondrial fission or autophagy resulted in increased death of myocytes overexpressing Bnip3. Moreover, Bnip3 promoted translocation of the E3 ubiquitin ligase Parkin to mitochondria, which was prevented in the presence of a Drp1 inhibitor. Interestingly, induction of autophagy by Bnip3 was reduced in Parkin-deficient myocytes. Thus our data suggest that induction of autophagy in response to Bnip3 is a protective response activated by the cell that involves Drp1-mediated mitochondrial fission and recruitment of Parkin.

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