scholarly journals Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca2+

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 612
Author(s):  
Seon Beom Song ◽  
Jin Sung Park ◽  
So Young Jang ◽  
Eun Seong Hwang
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Fission ◽  
Reactive Oxygen Species Generation ◽  
Oxygen Species ◽  
Mitochondrial Fragmentation ◽  
Mitochondrial Quality Control ◽  
Induced Changes ◽  
Amp Activated Protein Kinase ◽  
Nicotinamide Treatment ◽  
Kinase A

Mitochondrial autophagy (or mitophagy) is essential for mitochondrial quality control, which is critical for cellular and organismal health by attenuating reactive oxygen species generation and maintaining bioenergy homeostasis. Previously, we showed that mitophagy is activated in human cells through SIRT1 activation upon treatment of nicotinamide (NAM). Further, mitochondria are maintained as short fragments in the treated cells. In the current study, molecular pathways for NAM-induced mitochondrial fragmentation were sought. NAM treatment induced mitochondrial fission, at least in part by activating dynamin-1-like protein (Drp1), and this was through attenuation of the inhibitory phosphorylation at serine 637 (S637) of Drp1. This Drp1 hypo-phosphorylation was attributed to SIRT1-mediated activation of AMP-activated protein kinase (AMPK), which in turn induced a decrease in cellular levels of cyclic AMP (cAMP) and protein kinase A (PKA) activity, a kinase targeting S637 of Drp1. Furthermore, in NAM-treated cells, cytosolic Ca2+ was highly maintained; and, as a consequence, activity of calcineurin, a Drp1-dephosphorylating phosphatase, is expected to be elevated. These results suggest that NAD+-mediated SIRT1 activation facilitates mitochondrial fission through activation of Drp1 by suppressing its phosphorylation and accelerating its dephosphorylation. Additionally, it is suggested that there is a cycle of mitochondrial fragmentation and cytosolic Ca2+-mediated Drp1 dephosphorylation that may drive sustained mitochondrial fragmentation.

Abstract 568: Deletion of AMP-activated Protein Kinase-alpha Triggers Mitochondrial Fission and Endothelial Dysfunction

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Qqilong Wang ◽  
Zhonglin Xie ◽  
Huaiping Zhu ◽  
Ye Ding ◽  
Ming-Hui Zou
Keyword(s):  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Chronic Administration ◽  
Mitochondrial Fragmentation ◽  
Aortic Endothelium ◽  
Amp Activated Protein Kinase

Introduction: AMP-activated protein kinase (AMPK) has been reported to regulate mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which AMPK regulates mitochondrial dynamics remain poorly characterized. We hypothesized that AMPK deficiency regulates mitochondrial fission that will result in endothelial dysfunction. Methods/Results: Deletion of AMPKα2 resulted in defective autophagy, dynamin-related protein (Drp1) accumulation, and aberrant mitochondrial fragmentation in the aortic endothelium of mice. Furthermore, autophagy inhibition by chloroquine treatment or Atg7 small interfering RNA (siRNA) transfection upregulated Drp1 expression and triggered Drp1-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of Atg7 or chronic administration of rapamycin, the mammalian target of rapamycin kinase inhibitor, promoted Drp1 degradation and attenuated mitochondrial fission in AMPKα2 -/- mice, suggesting that defective autophagy contributes to enhanced Drp1 expression and mitochondrial fragmentation. Interesting, the genetic (Drp1 siRNA) or pharmacological (mdivi-1) inhibition of Drp1 ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas from AMPKα2 -/- mice. This suggests that aberrant Drp1 is responsible for enhanced mitochondrial fission and endothelial dysfunction in AMPKα knockout mice. Conclusions: Our results show that AMPKα deletion promoted mitochondrial fission in vascular endothelial cells by inhibiting the autophagy-dependent degradation of Drp1.

scholarly journals Adiponectin inhibits palmitate-induced apoptosis through suppression of reactive oxygen species in endothelial cells: involvement of cAMP/protein kinase A and AMP-activated protein kinase

2010 ◽  
Vol 207 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Ji-Eun Kim ◽  
Seung Eun Song ◽  
Yong-Woon Kim ◽  
Jong-Yeon Kim ◽  
Sung-Chul Park ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Protein Kinase ◽  
Inhibitory Effect ◽  
Ros Generation ◽  
Oxygen Species ◽  
Compound C ◽  
Induced Apoptosis ◽  
Amp Activated Protein Kinase ◽  
Kinase A

The present study examined whether adiponectin can inhibit palmitate-induced apoptosis, and also the associated mechanisms and signal transduction pathways in human umbilical vein endothelial cells. Cells treated with 500 μM palmitate for 48 h increased reactive oxygen species (ROS) generation and induced apoptosis. Treatment with antioxidant N-acetyl-l-cysteine (1 mM) and globular adiponectin (5 μg/ml) inhibited palmitate-induced ROS generation and apoptosis. The AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 1 mM), and cAMP activators forskolin (10 μM) and cholera toxin (200 ng/ml) also displayed the same effects. The inhibitory effects of adiponectin on ROS generation and apoptosis were reversed by the AMPK inhibitor compound C (40 μM), cAMP inhibitor SQ22536 (50 μM), and protein kinase A (PKA) inhibitor H-89 (10 μM). The inhibitory effect of forskolin on palmitate-induced apoptosis was reversed by compound C, whereas the inhibitory effect of AICAR was not reversed by SQ22536 and H-89. AICAR and forskolin could not inhibit palmitate-induced apoptosis in cells treated with dominant-negative AMPK. Forskolin increased phosphorylated AMPK at both Thr-172 and Ser-485/491. These results suggest that adiponectin inhibits palmitate-induced apoptosis by suppression of ROS generation via both the cAMP/PKA and AMPK pathways. Interaction between cAMP/PKA and AMPK pathways may be involved.

scholarly journals AMP-activated protein kinase: a remarkable contributor to preserve a healthy heart against ROS injury

2021 ◽  
Author(s):  
Alice Marino ◽  
Derek J. Hausenloy ◽  
Ioanna Andreadou ◽  
Sandrine Horman ◽  
Luc Bertrand ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Amp Activated Protein Kinase ◽  
Kinase A

scholarly journals Differential regulation of AMP-activated protein kinase in healthy and cancer cells explains why V-ATPase inhibition selectively kills cancer cells

2019 ◽  
Vol 294 (46) ◽  
pp. 17239-17248
Author(s):  
Karin Bartel ◽  
Rolf Müller ◽  
Karin von Schwarzenberg
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Reactive Oxygen Species Production ◽  
Differential Regulation ◽  
Oxygen Species ◽  
Atpase Inhibitors ◽  
Species Production ◽  
Amp Activated Protein Kinase ◽  
Atpase Inhibition

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic hub regulating various pathways involved in tumor metabolism. Here we report that vacuolar H+-ATPase (V-ATPase) inhibition differentially affects regulation of AMPK in tumor and nontumor cells and that this differential regulation contributes to the selectivity of V-ATPase inhibitors for tumor cells. In nonmalignant cells, the V-ATPase inhibitor archazolid increased phosphorylation and lysosomal localization of AMPK. We noted that AMPK localization has a prosurvival role, as AMPK silencing decreased cellular growth rates. In contrast, in cancer cells, we found that AMPK is constitutively active and that archazolid does not affect its phosphorylation and localization. Moreover, V-ATPase–independent AMPK induction in tumor cells protected them from archazolid-induced cytotoxicity, further underlining the role of AMPK as a prosurvival mediator. These observations indicate that AMPK regulation is uncoupled from V-ATPase activity in cancer cells and that this makes them more susceptible to cell death induction by V-ATPase inhibitors. In both tumor and healthy cells, V-ATPase inhibition induced a distinct metabolic regulatory cascade downstream of AMPK, affecting ATP and NADPH levels, glucose uptake, and reactive oxygen species production. We could attribute the prosurvival effects to AMPK's ability to maintain redox homeostasis by inhibiting reactive oxygen species production and maintaining NADPH levels. In summary, the results of our work indicate that V-ATPase inhibition has differential effects on AMPK-mediated metabolic regulation in cancer and healthy cells and explain the tumor-specific cytotoxicity of V-ATPase inhibition.

scholarly journals Role of Binding and Nucleoside Diphosphate Kinase A (NDPK‐A) in the Regulation of CFTR by AMP‐Activated Protein Kinase (AMPK)

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
J Darwin King ◽  
Jeffrey Lee ◽  
Claudia E. Rieman ◽  
Anil Mehta ◽  
Richmond Muimo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nucleoside Diphosphate Kinase ◽  
Amp Activated Protein Kinase ◽  
Kinase A

AMP-Activated Protein Kinase: A Metabolic Stress Sensor in the Heart

2015 ◽  
pp. 187-225
Author(s):  
Martin Pelosse ◽  
Malgorzata Tokarska-Schlattner ◽  
Uwe Schlattner
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Metabolic Stress ◽  
Stress Sensor ◽  
Amp Activated Protein Kinase ◽  
Kinase A
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