scholarly journals Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy

2016 ◽  
Vol 215 (6) ◽  
pp. 779-788 ◽  
Author(s):  
Ariadne Vlahakis ◽  
Nerea Lopez Muniozguren ◽  
Ted Powers
Keyword(s):  
Oxidative Stress ◽  
Amino Acid ◽  
Calcium Channel ◽  
Mitochondrial Respiration ◽  
Nitrogen Availability ◽  
Protein Complexes ◽  
Regulatory Protein ◽  
Mitochondrial Oxidative Stress ◽  
General Amino Acid Control ◽  
Calcium Dependent

Autophagy is a catabolic process that recycles cytoplasmic contents and is crucial for cell survival during stress. The target of rapamycin (TOR) kinase regulates autophagy as part of two distinct protein complexes, TORC1 and TORC2. TORC1 negatively regulates autophagy according to nitrogen availability. In contrast, TORC2 functions as a positive regulator of autophagy during amino acid starvation, via its target kinase Ypk1, by repressing the activity of the calcium-dependent phosphatase calcineurin and promoting the general amino acid control (GAAC) response. Precisely how TORC2-Ypk1 signaling regulates calcineurin within this pathway remains unknown. Here we demonstrate that activation of calcineurin requires Mid1, an endoplasmic reticulum–localized calcium channel regulatory protein implicated in the oxidative stress response. We find that normal mitochondrial respiration is perturbed in TORC2-Ypk1–deficient cells, which results in the accumulation of mitochondrial-derived reactive oxygen species that signal to Mid1 to activate calcineurin, thereby inhibiting the GAAC response and autophagy. These findings describe a novel pathway involving TORC2, mitochondrial oxidative stress, and calcium homeostasis for autophagy regulation.

scholarly journals Condensin II protein dysfunction impacts mitochondrial respiration and mitochondrial oxidative stress responses

2019 ◽  
Vol 132 (22) ◽  
pp. jcs233783
Author(s):  
Emily Deutschman ◽  
Jacqueline R. Ward ◽  
Avinash Kumar ◽  
Greeshma Ray ◽  
Nicole Welch ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Mitochondrial Respiration ◽  
Mitochondrial Oxidative Stress ◽  
Protein Dysfunction ◽  
Oxidative Stress Responses

scholarly journals Impaired peripheral mononuclear cell metabolism in patients at risk of developing sepsis: A cohort study

2020 ◽  
Author(s):  
Velma Herwanto ◽  
Ya Wang ◽  
Maryam Shojaei ◽  
Alamgir Khan ◽  
Kevin Lai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Level ◽  
Mitochondrial Respiration ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Cellular Metabolism ◽  
P Value ◽  
Mitochondrial Oxidative Stress ◽  
Oxidative Stress Level

AbstractPurposeDysregulated immune response is a key driver of disease progression in sepsis and known to be associated with impaired cellular metabolism. This association has been studied mostly in the late stage sepsis patients. Here, we investigate whether such impairment in cellular metabolism is present in uncomplicated infection patients who do not develop sepsis.MethodsForty sepsis (fulfilled Sepsis-3 criteria) and 27 uncomplicated infection patients were recruited from the emergency department along with 20 healthy volunteers. Whole blood was collected for measurement of gene expression, cytokine levels and cellular metabolic functions (including mitochondrial respiration, oxidative stress and apoptosis).ResultsOur analysis revealed the impairment of mitochondrial respiration in uncomplicated infection and sepsis patients (p value <0.05), with greater degree of impairment noted in the established sepsis. The impairment was significantly correlated with increased mitochondrial oxidative stress level; the latter was increased in uncomplicated infection and more so in established sepsis patients. Further analysis revealed that the oxidative stress level correlated significantly with cytokine level (tumor necrosis factor-α) and gene expression levels (CYCS, TP53, SLC24A24 and TSPO).ConclusionsThese findings suggest that impaired immune cell metabolism is present in infection patients without presenting sepsis, thereby opening potential window for early diagnosis and intervention (e.g. antioxidant therapy) in such patients.

scholarly journals Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia

2020 ◽  
Vol 318 (2) ◽  
pp. R256-R262 ◽  
Author(s):  
Venkata Ramana Vaka ◽  
Mark W. Cunningham ◽  
Evangeline Deer ◽  
Michael Franks ◽  
Tarek Ibrahim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Rat Model ◽  
Mitochondrial Respiration ◽  
Umbilical Vein ◽  
Type I ◽  
Sprague Dawley ◽  
Mitochondrial Oxidative Stress ◽  
Umbilical Vein Endothelial Cells

Preeclampsia (PE) is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and many other characteristics of PE. We have previously shown that mitochondrial oxidative stress (mtROS) is a newly described PE characteristic exhibited by the RUPP rat that contributes to hypertension. However, the factors that cause mtROS in PE or RUPP are unknown. Thus, the objective of the current study is to use pharmacologic inhibition of AT1-AAs to examine their role in mtROS in the RUPP rat model of PE. AT1-AA inhibition in RUPP rats was achieved by administration of an epitope-binding peptide (′n7AAc′). Female Sprague-Dawley rats were divided into the following two groups: RUPP and RUPP + AT1-AA inhibition (RUPP + ′n7AAc′). On day 14 of gestation (GD), RUPP surgery was performed; ′n7AAc′ peptide (2 µg/μL) was administered by miniosmotic pumps in a subset of RUPP rats; and on GD19, sera, placentas, and kidneys were collected. mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. Placental and renal mitochondrial respiration and mtROS were improved in RUPP + ′n7AAc′ rats compared with RUPP controls. Moreover, endothelial cells (human umbilical vein endothelial cells) treated with RUPP + ′n7AAc′ sera exhibited less mtROS compared with those treated with RUPP sera. Overall, our findings suggest that AT1-AA signaling is one stimulus of mtROS during PE.

Abstract 283: Angiotensin II Induces Oxidative Stress Through ADP-ribose-Transient Receptor Potential Melastatin 2-Dependent Mechanisms In Human Microvascular Endothelial Cells: Role Of AT2 Receptor.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Maria G Dulak-Lis ◽  
Aurelie D Nguyen ◽  
Carol J Jenkins ◽  
Augusto C Montezano ◽  
Rhian M Touyz
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Calcium Channel ◽  
Superoxide Production ◽  
Microvascular Endothelial Cells ◽  
Ros Generation ◽  
H2o2 Production ◽  
Ang Ii ◽  
Calcium Dependent ◽  
Microvascular Endothelial

Endothelial dysfunction is associated with oxidative stress and dysregulation of calcium signalling. We previously demonstrated that calcium dependent Nox5 is regulated by Ang II and may be implicated in vascular damage in hypertension. Elevation of intracellular free calcium concentration ([Ca2+]i) influences oxidative stress, which may be related to activation of redox sensitive calcium channel TRPM2. Here, we postulated that in human microvascular endothelial cells (HMEC), Ang II induces ROS generation through TRPM2-dependent processes. HMECs were stimulated with either Ang II (100 nM) or H2O2 (1 mM). ROS production was measured by lucigenin (superoxide) and amplex red (H2O2); redox sensitive MAPKs/eNOS activation by immunoblotting; and AT1R/AT2R mRNA by Q PCR. In some experiments, the following inhibitors were used: aminoethoxydiphenyl borate (APB, TRPM2/SERCA/IP3R inhibitor), N (p amylcinnamoyl)anthranilic acid (ACA, TRPM2/PLA2 inhibitor), 8-bromo-cADP-ribose (8 Br-cADPR, ADPR antagonist), 3,4-Dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline (DPQ, poly-ADPR polymerase inhibitor) and PD123319 (AT2R antagonist). In hmECs, Ang II increased superoxide levels (1.9±0.2 fold, p<0.05 vs. vehicle), an effect blocked by APB, ACA, 8-Br-cADPR, DPQ and PD123319. In addition, Ang II-induced increase in H2O2 production (1.6±0.21 fold, p<0.05 vs. vehicle) was inhibited by AT2R antagonism. Ang II stimulation increased ERK1/2 activation (185%), but not p38, through AT2R-dependent mechanisms (p<0.05). AT2R, but not AT1R was expressed in HMECs. H2O2, an activator of TRPM2, decreased superoxide production (25%) and increased MAPKs (p38: 82%; ERK1/2: 40%; JNK: 36%), as well as, eNOS (24%) activation, p<0.05. In addition, ROS formation by Ang II was measured in the presence of L-type calcium channel blocker diltiazem, which also blocked Ang II effects on superoxide production. In conclusion, our data demonstrate that Ang II-induced oxidative stress and redox-sensitive MAPK activation in hmEC cells may involve TRPM2 and calcium-dependent signalling, which are mediated via AT2R. Our findings identify a novel signalling pathways whereby Ang II/AT2R regulates endothelial cell ROS generation through TRPM2.

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