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Sachin A. Gupte - One of the best experts on this subject based on the ideXlab platform.

  • microrna 140 is elevated and Mitofusin 1 is downregulated in the right ventricle of the sugen5416 hypoxia normoxia model of pulmonary arterial hypertension
    American Journal of Physiology-heart and Circulatory Physiology, 2016
    Co-Authors: Sachindra R. Joshi, Vidhi Dhagia, Salina Gairhe, John G. Edwards, Ivan F. Mcmurtry, Sachin A. Gupte
    Abstract:

    Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR-21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (>2-fold; P 2-fold; P 2-fold; P 2-fold in LV+S compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of Mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LV+S of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.

  • microrna 140 is elevated and Mitofusin 1 is downregulated in the right ventricle of the sugen5416 hypoxia normoxia model of pulmonary arterial hypertension
    American Journal of Physiology-heart and Circulatory Physiology, 2016
    Co-Authors: Sachindra R. Joshi, Vidhi Dhagia, Salina Gairhe, John G. Edwards, Ivan F. Mcmurtry, Sachin A. Gupte
    Abstract:

    We show that in an experimental model of severe pulmonary arterial hypertension, miR-140 is significantly upregulated in the hypertrophic right ventricle, and its target protein Mitofusin-1 is significantly downregulated. The increase in miR-140 is significantly correlated with increase in right ventricular systolic pressure and right ventricle hypertrophy.

  • MicroRNA-140 is elevated and Mitofusin-1 is downregulated in the right ventricle of the Sugen5416/Hypoxia/Normoxia model of pulmonary arterial hypertension.
    American journal of physiology. Heart and circulatory physiology, 2016
    Co-Authors: Sachindra R. Joshi, Vidhi Dhagia, Salina Gairhe, John G. Edwards, Ivan F. Mcmurtry, Sachin A. Gupte
    Abstract:

    Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR-21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (>2-fold; P 2-fold; P 2-fold; P 2-fold in LV+S compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of Mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LV+S of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.

Hyeseong Cho - One of the best experts on this subject based on the ideXlab platform.

  • Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization
    Cellular signalling, 2017
    Co-Authors: Nguyen Thi Kim Oanh, Yong-yea Park, Hyeseong Cho
    Abstract:

    Mitochondria are highly dynamic organelles that change size and morphology by fusing together or dividing through fission. In response to cellular cues, signaling cascades may post-translationally modify mitochondria-shaping proteins, which lead to a change in mitochondria morphology. Here we show that nicotinamide (NAM), an inhibitor of sirtuin deacetylases, promotes degradation of mitochondria fusion protein Mitofusin 1 (MFN1), suggesting that acetylation status of MFN1 is important for its protein stability. TIP60 but not PCAF acetyltransferase caused a reduction of MFN1 level. Meanwhile, siRNA-mediated knockdown of SIRT1 deacetylase caused a significant reduction of MFN1 whereas over-expression of SIRT1 increased its level in 293T cells. In vitro acetylation experiments showed that TIP60 increased the acetylation of MFN1 that was abolished by co-existence of SIRT1. Notably, MFN1 and SIRT1 levels were accumulated, along with mitochondria elongation under hypoxic conditions. Thus, the data suggest that mitochondria elongation under hypoxic condition is regulated through SIRT1-mediated MFN1 deacetylation and accumulation. The data provide an insight in the maintenance of cellular homeostasis through mitochondria morphological change.

  • Mitofusin 1 is degraded at G2/M phase through ubiquitylation by MARCH5
    Cell division, 2012
    Co-Authors: Yong-yea Park, Hyeseong Cho
    Abstract:

    Background Mitochondria exhibit a dynamic morphology in cells and their biogenesis and function are integrated with the nuclear cell cycle. In mitotic cells, the filamentous network structure of mitochondria takes on a fragmented form. To date, however, whether mitochondrial fusion activity is regulated in mitosis has yet to be elucidated.

  • Mitofusin 1 is degraded at g2 m phase through ubiquitylation by march5
    Cell Division, 2012
    Co-Authors: Yong-yea Park, Hyeseong Cho
    Abstract:

    Background Mitochondria exhibit a dynamic morphology in cells and their biogenesis and function are integrated with the nuclear cell cycle. In mitotic cells, the filamentous network structure of mitochondria takes on a fragmented form. To date, however, whether mitochondrial fusion activity is regulated in mitosis has yet to be elucidated.

  • loss of march5 mitochondrial e3 ubiquitin ligase induces cellular senescence through dynamin related protein 1 and Mitofusin 1
    Journal of Cell Science, 2010
    Co-Authors: Yong-yea Park, Mariusz Karbowski, Richard J Youle, Seungmin Lee, Albert Neutzner, Hyeseong Cho
    Abstract:

    Mitochondria constantly divide and combine through fission and fusion activities. MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and Mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion. However, how these interactions control mitochondrial dynamics, and cellular function has remained obscure. Here, we show that shRNA-mediated MARCH5 knockdown promoted the accumulation of highly interconnected and elongated mitochondria. Cells transfected with MARCH5 shRNA or a MARCH5 RING domain mutant displayed cellular enlargement and flattening accompanied by increased senescence-associated β-galactosidase (SA-β-Gal) activity, indicating that these cells had undergone cellular senescence. Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. Introduction of Mfn1T109A, a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-β-Gal activity. Moreover, the aberrant mitochondrial phenotypes in MARCH5-RNAi cells were reversed by ectopic expression of Drp1, but not by hFis1, and reversion of the mitochondria morphology in MARCH5-depleted cells was accompanied by a reduction in SA-β-Gal activity. Collectively, our data indicate that the lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria.

  • Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and Mitofusin 1.
    Journal of cell science, 2010
    Co-Authors: Yong-yea Park, Mariusz Karbowski, Richard J Youle, Seungmin Lee, Albert Neutzner, Hyeseong Cho
    Abstract:

    Mitochondria constantly divide and combine through fission and fusion activities. MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and Mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion. However, how these interactions control mitochondrial dynamics, and cellular function has remained obscure. Here, we show that shRNA-mediated MARCH5 knockdown promoted the accumulation of highly interconnected and elongated mitochondria. Cells transfected with MARCH5 shRNA or a MARCH5 RING domain mutant displayed cellular enlargement and flattening accompanied by increased senescence-associated beta-galactosidase (SA-beta-Gal) activity, indicating that these cells had undergone cellular senescence. Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. Introduction of Mfn1(T109A), a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-beta-Gal activity. Moreover, the aberrant mitochondrial phenotypes in MARCH5-RNAi cells were reversed by ectopic expression of Drp1, but not by hFis1, and reversion of the mitochondria morphology in MARCH5-depleted cells was accompanied by a reduction in SA-beta-Gal activity. Collectively, our data indicate that the lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria.

Jia Shi - One of the best experts on this subject based on the ideXlab platform.

  • Role of PKCα/HO-1 signaling pathway in endotoxin-induced damage to alveolar macrophages of rats: the relationship with Mitofusin-1
    Chinese Journal of Anesthesiology, 2017
    Co-Authors: Man Wang, Dan Wang, Jia Shi
    Abstract:

    Objective To evaluate the role of protein kinase C α (PKCα)/heme oxygenase-1 (HO-1) signaling pathway in endotoxin-induced damage to alveolar macrophages and the relationship with Mitofusin-1 (Mfn1) in rats. Methods Rat alveolar macrophages NR8383 cells cultured in vitro were seeded in 96-well plates at a density of 1×104 cells/ml.NR8383 cells were divided into 5 groups (n=15 each) using a random number table: control group (group C), endotoxin challenge model group (group E), PKCα inhibitor Go6976 group (group G), PKCα agonist PMA group (group P) and dimethyl sulfoxide group (group D). NR8383 cells were stimulated with 10 μg/ml lipopolysaccharide (LPS) to establish the model of endotoxin challenge in alveolar macrophages.In G, P and D groups, cells were pretreated with 5 μmol/L Go6976, 100 nmol/L PMA and 0.1% dimethyl sulfoxide, respectively, for 30 min starting from 30 min before stimulation with LPS, and 10 μg/ml LPS was then given.The cells were collected after 24 h of incubation for measurement of malondialdehyde (MDA) and reactive oxygen species (ROS) contents, superoxide dismutase (SOD) activity and expression of PKCα, HO-1 and Mfn1 protein and mRNA (by fluorescent quantitative polymerase chain reaction or Western blot). Results Compared with group C, MDA and ROS contents were significantly increased, the SOD activity was decreased, the expression of PKCα and HO-1 protein and mRNA was up-regulated, and the expression of Mfn1 protein and mRNA was down-regulated in E, G, P and D groups (P 0.05). Conclusion Promotion of Mfn1 expression following PKCα/HO-1 signaling pathway activation is the endogenous protective mechanism of endotoxin-induced damage to alveolar macrophages of rats. Key words: Protein kinase C-alpha; Heme oxygenase-1; Endotoxins; Mitochondrial proteins; Membrane fusion proteins

  • role of pkcα ho 1 signaling pathway in endotoxin induced damage to alveolar macrophages of rats the relationship with Mitofusin 1
    Chinese Journal of Anesthesiology, 2017
    Co-Authors: Man Wang, Dan Wang, Jia Shi
    Abstract:

    Objective To evaluate the role of protein kinase C α (PKCα)/heme oxygenase-1 (HO-1) signaling pathway in endotoxin-induced damage to alveolar macrophages and the relationship with Mitofusin-1 (Mfn1) in rats. Methods Rat alveolar macrophages NR8383 cells cultured in vitro were seeded in 96-well plates at a density of 1×104 cells/ml.NR8383 cells were divided into 5 groups (n=15 each) using a random number table: control group (group C), endotoxin challenge model group (group E), PKCα inhibitor Go6976 group (group G), PKCα agonist PMA group (group P) and dimethyl sulfoxide group (group D). NR8383 cells were stimulated with 10 μg/ml lipopolysaccharide (LPS) to establish the model of endotoxin challenge in alveolar macrophages.In G, P and D groups, cells were pretreated with 5 μmol/L Go6976, 100 nmol/L PMA and 0.1% dimethyl sulfoxide, respectively, for 30 min starting from 30 min before stimulation with LPS, and 10 μg/ml LPS was then given.The cells were collected after 24 h of incubation for measurement of malondialdehyde (MDA) and reactive oxygen species (ROS) contents, superoxide dismutase (SOD) activity and expression of PKCα, HO-1 and Mfn1 protein and mRNA (by fluorescent quantitative polymerase chain reaction or Western blot). Results Compared with group C, MDA and ROS contents were significantly increased, the SOD activity was decreased, the expression of PKCα and HO-1 protein and mRNA was up-regulated, and the expression of Mfn1 protein and mRNA was down-regulated in E, G, P and D groups (P 0.05). Conclusion Promotion of Mfn1 expression following PKCα/HO-1 signaling pathway activation is the endogenous protective mechanism of endotoxin-induced damage to alveolar macrophages of rats. Key words: Protein kinase C-alpha; Heme oxygenase-1; Endotoxins; Mitochondrial proteins; Membrane fusion proteins

  • Role of PI3K/Akt signaling pathway in carbon monoxide-induced up-regulation of Mitofusin-1 expression in endotoxin-challenged rat alveolar macrophages
    Chinese Journal of Anesthesiology, 2017
    Co-Authors: Jia Shi, Dan Wang, Lirong Gong, Shu′an Dong, Yuan Zhang
    Abstract:

    Objective To evaluate the role of phosphatidylinositol 3-kinase/serine-threonine kinase(PI3K/Akt)signaling pathway in carbon monoxide(CO)-induced up-regulation of the Mitofusin-1(Mfn1)expression in endotoxin-challenged rat alveolar macrophages. Methods Alveolar macrophages obtained from the rats aged 12-20 weeks were subcultured and seeded in 96 well plates at a density of 4×104 cells/ml.After being cultured for 24 h, the cells were divided into 4 groups(n=10 each)using a random number table: control group(group C), endotoxin group(group L), lipopolysaccharide(LPS)+ CO-releasing molecule-2(CORM-2)group(group L+ C)and LPS+ CORM-2+ PI3K inhibitor LY294002 group(group L+ C+ LY). Cells were cultured normally in group C. Cells were stimulated by using LPS 10 μg/ml in L, L+ C and L+ C+ LY groups.In group L+ C, CORM-2 100 μmol was given at 1 h before stimulation with LPS.In group L+ C+ LY, LY294002 20 μg and CORM-2 100 μmol were given at 1.5 and 1.0 h before stimulation with LPS, respectively.The cells were continuously incubated for 24 h after the end of treatment.The concentrations of tumor necrosis factor-α(TNF-α)and interleukin-10(IL-10)in the supernatant were determined by enzyme-linked immunosorbent assay.The expression of PI3K, phosphorylated Akt(p-Akt)and Mfn1 in cells was measured by real-time polymerase chain reaction and Western blot. Results Compared with group C, the concentration of TNF-α was significantly increased, and the IL-10 concentration was decreased in L, L+ C and L+ C+ LY groups(P

  • role of pi3k akt signaling pathway in carbon monoxide induced up regulation of Mitofusin 1 expression in endotoxin challenged rat alveolar macrophages
    Chinese Journal of Anesthesiology, 2017
    Co-Authors: Jia Shi, Shu-an Dong, Dan Wang, Lirong Gong, Yuan Zhang
    Abstract:

    Objective To evaluate the role of phosphatidylinositol 3-kinase/serine-threonine kinase(PI3K/Akt)signaling pathway in carbon monoxide(CO)-induced up-regulation of the Mitofusin-1(Mfn1)expression in endotoxin-challenged rat alveolar macrophages. Methods Alveolar macrophages obtained from the rats aged 12-20 weeks were subcultured and seeded in 96 well plates at a density of 4×104 cells/ml.After being cultured for 24 h, the cells were divided into 4 groups(n=10 each)using a random number table: control group(group C), endotoxin group(group L), lipopolysaccharide(LPS)+ CO-releasing molecule-2(CORM-2)group(group L+ C)and LPS+ CORM-2+ PI3K inhibitor LY294002 group(group L+ C+ LY). Cells were cultured normally in group C. Cells were stimulated by using LPS 10 μg/ml in L, L+ C and L+ C+ LY groups.In group L+ C, CORM-2 100 μmol was given at 1 h before stimulation with LPS.In group L+ C+ LY, LY294002 20 μg and CORM-2 100 μmol were given at 1.5 and 1.0 h before stimulation with LPS, respectively.The cells were continuously incubated for 24 h after the end of treatment.The concentrations of tumor necrosis factor-α(TNF-α)and interleukin-10(IL-10)in the supernatant were determined by enzyme-linked immunosorbent assay.The expression of PI3K, phosphorylated Akt(p-Akt)and Mfn1 in cells was measured by real-time polymerase chain reaction and Western blot. Results Compared with group C, the concentration of TNF-α was significantly increased, and the IL-10 concentration was decreased in L, L+ C and L+ C+ LY groups(P<0.05). Compared with group L, the concentration of IL-10 was significantly increased, the TNF-α concentration was decreased, and the expression of PI3K, p-Akt and Mfn1 was up-regulated in group L+ C(P<0.05). Compared with group L+ C, the concentration of IL-10 was significantly decreased, the TNF-α concentration was increased, and the expression of PI3K, p-Akt and Mfn1 was down-regulated in group L+ C+ LY(P<0.05). Conclusion PI3K/Akt signaling pathway is involved in CO-induced up-regulation of Mfn1 expression in endotoxin-challenged rat alveolar macrophages. Key words: Carbon monoxide; Mitochondrial proteins; 1-Phosphatidylinositol 3-kinase; Protein-serine-threonine kinases

  • Effect of Heme Oxygenase-1 on Mitofusin-1 protein in LPS-induced ALI/ARDS in rats.
    Scientific reports, 2016
    Co-Authors: Ying Wang, Shu-an Dong, Dan Wang, Lirong Gong, Jia Shi, Yuan Zhang, Daquan Liu
    Abstract:

    Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common and important oxidative stress in the lung. Mitochondrial fusion responds to the normal morphology and function of cells and is finely regulated by mitochondrial fusion proteins, such as Mitofusin-1 protein (Mfn1), Mitofusin-2 protein (Mfn2) and optical atrophy 1 (OPA1). Additionally, Mfn1 has been identified as the most important protein in mitochondrial fusion. Heme oxygenase-1 (HO-1) is a stress-inducible protein that plays a critical role in protecting against oxidative stress. However, whether the protection of HO-1 is related to mitochondrial fusion is still a question. Thus, our in vitro and in vivo experiments aimed to identify the relationship between HO-1 and Mfn1. Here, we used Hemin and ZnPP-IX as treatments in an in vivo experiment. Then, HO-1 and Mfn1 were measured using RT-PCR and Western blotting. Supernatants were analyzed for MDA, SOD, and ROS. Our results implied that HO-1 upregulation suppressed oxidative stress induced by LPS, and the possible mechanism could be associated with Mfn1 and the PI3K/Akt pathway.

Sachindra R. Joshi - One of the best experts on this subject based on the ideXlab platform.

  • microrna 140 is elevated and Mitofusin 1 is downregulated in the right ventricle of the sugen5416 hypoxia normoxia model of pulmonary arterial hypertension
    American Journal of Physiology-heart and Circulatory Physiology, 2016
    Co-Authors: Sachindra R. Joshi, Vidhi Dhagia, Salina Gairhe, John G. Edwards, Ivan F. Mcmurtry, Sachin A. Gupte
    Abstract:

    Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR-21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (>2-fold; P 2-fold; P 2-fold; P 2-fold in LV+S compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of Mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LV+S of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.

  • microrna 140 is elevated and Mitofusin 1 is downregulated in the right ventricle of the sugen5416 hypoxia normoxia model of pulmonary arterial hypertension
    American Journal of Physiology-heart and Circulatory Physiology, 2016
    Co-Authors: Sachindra R. Joshi, Vidhi Dhagia, Salina Gairhe, John G. Edwards, Ivan F. Mcmurtry, Sachin A. Gupte
    Abstract:

    We show that in an experimental model of severe pulmonary arterial hypertension, miR-140 is significantly upregulated in the hypertrophic right ventricle, and its target protein Mitofusin-1 is significantly downregulated. The increase in miR-140 is significantly correlated with increase in right ventricular systolic pressure and right ventricle hypertrophy.

  • MicroRNA-140 is elevated and Mitofusin-1 is downregulated in the right ventricle of the Sugen5416/Hypoxia/Normoxia model of pulmonary arterial hypertension.
    American journal of physiology. Heart and circulatory physiology, 2016
    Co-Authors: Sachindra R. Joshi, Vidhi Dhagia, Salina Gairhe, John G. Edwards, Ivan F. Mcmurtry, Sachin A. Gupte
    Abstract:

    Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR-21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (>2-fold; P 2-fold; P 2-fold; P 2-fold in LV+S compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of Mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LV+S of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.

Yong-yea Park - One of the best experts on this subject based on the ideXlab platform.

  • Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization
    Cellular signalling, 2017
    Co-Authors: Nguyen Thi Kim Oanh, Yong-yea Park, Hyeseong Cho
    Abstract:

    Mitochondria are highly dynamic organelles that change size and morphology by fusing together or dividing through fission. In response to cellular cues, signaling cascades may post-translationally modify mitochondria-shaping proteins, which lead to a change in mitochondria morphology. Here we show that nicotinamide (NAM), an inhibitor of sirtuin deacetylases, promotes degradation of mitochondria fusion protein Mitofusin 1 (MFN1), suggesting that acetylation status of MFN1 is important for its protein stability. TIP60 but not PCAF acetyltransferase caused a reduction of MFN1 level. Meanwhile, siRNA-mediated knockdown of SIRT1 deacetylase caused a significant reduction of MFN1 whereas over-expression of SIRT1 increased its level in 293T cells. In vitro acetylation experiments showed that TIP60 increased the acetylation of MFN1 that was abolished by co-existence of SIRT1. Notably, MFN1 and SIRT1 levels were accumulated, along with mitochondria elongation under hypoxic conditions. Thus, the data suggest that mitochondria elongation under hypoxic condition is regulated through SIRT1-mediated MFN1 deacetylation and accumulation. The data provide an insight in the maintenance of cellular homeostasis through mitochondria morphological change.

  • Mitofusin 1 is degraded at G2/M phase through ubiquitylation by MARCH5
    Cell division, 2012
    Co-Authors: Yong-yea Park, Hyeseong Cho
    Abstract:

    Background Mitochondria exhibit a dynamic morphology in cells and their biogenesis and function are integrated with the nuclear cell cycle. In mitotic cells, the filamentous network structure of mitochondria takes on a fragmented form. To date, however, whether mitochondrial fusion activity is regulated in mitosis has yet to be elucidated.

  • Mitofusin 1 is degraded at g2 m phase through ubiquitylation by march5
    Cell Division, 2012
    Co-Authors: Yong-yea Park, Hyeseong Cho
    Abstract:

    Background Mitochondria exhibit a dynamic morphology in cells and their biogenesis and function are integrated with the nuclear cell cycle. In mitotic cells, the filamentous network structure of mitochondria takes on a fragmented form. To date, however, whether mitochondrial fusion activity is regulated in mitosis has yet to be elucidated.

  • loss of march5 mitochondrial e3 ubiquitin ligase induces cellular senescence through dynamin related protein 1 and Mitofusin 1
    Journal of Cell Science, 2010
    Co-Authors: Yong-yea Park, Mariusz Karbowski, Richard J Youle, Seungmin Lee, Albert Neutzner, Hyeseong Cho
    Abstract:

    Mitochondria constantly divide and combine through fission and fusion activities. MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and Mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion. However, how these interactions control mitochondrial dynamics, and cellular function has remained obscure. Here, we show that shRNA-mediated MARCH5 knockdown promoted the accumulation of highly interconnected and elongated mitochondria. Cells transfected with MARCH5 shRNA or a MARCH5 RING domain mutant displayed cellular enlargement and flattening accompanied by increased senescence-associated β-galactosidase (SA-β-Gal) activity, indicating that these cells had undergone cellular senescence. Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. Introduction of Mfn1T109A, a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-β-Gal activity. Moreover, the aberrant mitochondrial phenotypes in MARCH5-RNAi cells were reversed by ectopic expression of Drp1, but not by hFis1, and reversion of the mitochondria morphology in MARCH5-depleted cells was accompanied by a reduction in SA-β-Gal activity. Collectively, our data indicate that the lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria.

  • Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and Mitofusin 1.
    Journal of cell science, 2010
    Co-Authors: Yong-yea Park, Mariusz Karbowski, Richard J Youle, Seungmin Lee, Albert Neutzner, Hyeseong Cho
    Abstract:

    Mitochondria constantly divide and combine through fission and fusion activities. MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and Mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion. However, how these interactions control mitochondrial dynamics, and cellular function has remained obscure. Here, we show that shRNA-mediated MARCH5 knockdown promoted the accumulation of highly interconnected and elongated mitochondria. Cells transfected with MARCH5 shRNA or a MARCH5 RING domain mutant displayed cellular enlargement and flattening accompanied by increased senescence-associated beta-galactosidase (SA-beta-Gal) activity, indicating that these cells had undergone cellular senescence. Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. Introduction of Mfn1(T109A), a GTPase-deficient mutant form of Mfn1, into MARCH5-RNAi cells not only disrupted mitochondrial elongation, but also abolished the increase in SA-beta-Gal activity. Moreover, the aberrant mitochondrial phenotypes in MARCH5-RNAi cells were reversed by ectopic expression of Drp1, but not by hFis1, and reversion of the mitochondria morphology in MARCH5-depleted cells was accompanied by a reduction in SA-beta-Gal activity. Collectively, our data indicate that the lack of MARCH5 results in mitochondrial elongation, which promotes cellular senescence by blocking Drp1 activity and/or promoting accumulation of Mfn1 at the mitochondria.