scholarly journals Mitochondrial Oxidative Stress and Calcium-Dependent Permeability Transition are Key Players in the Mechanisms of Statins-Associated Side Effects

2018 ◽  
Author(s):  
Estela N.B. Busanello ◽  
Ana C. Marques ◽  
Estela Lorza-Gil ◽  
Helena C.F. de Oliveira ◽  
Anibal E. Vercesi
Keyword(s):  
Oxidative Stress ◽  
Side Effects ◽  
Permeability Transition ◽  
Mitochondrial Oxidative Stress ◽  
Calcium Dependent ◽  
Key Players

scholarly journals Mitochondrial oxidative stress induced by Ca2+ and monoamines: different behaviour of liver and brain mitochondria in undergoing permeability transition

Amino Acids ◽  
2011 ◽  
Vol 42 (2-3) ◽  
pp. 751-759 ◽  
Author(s):  
Silvia Grancara ◽  
Valentina Battaglia ◽  
Pamela Martinis ◽  
Nikenza Viceconte ◽  
Enzo Agostinelli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Permeability Transition ◽  
Brain Mitochondria ◽  
Mitochondrial Oxidative Stress

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.

Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells

2015 ◽  
Vol 308 (11) ◽  
pp. E933-E941 ◽  
Author(s):  
Tuyet Thi Nguyen ◽  
Xianglan Quan ◽  
Kyu-Hee Hwang ◽  
Shanhua Xu ◽  
Ranjan Das ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Stress Proteins ◽  
Mitochondrial Permeability Transition ◽  
Islet Cells ◽  
Atp Synthesis ◽  
Permeability Transition ◽  
Insulin Content ◽  
Superoxide Generation ◽  
Mitochondrial Oxidative Stress

Inorganic phosphate (P i) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, P i transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated P i concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have investigated the effect of P i on secretory function and apoptosis in INS-1E clonal β-cells and rat pancreatic islets. Elevated extracellular P i (1∼5 mM) increased the mitochondrial membrane potential (ΔΨm), superoxide generation, caspase activation, and cell death. Depolarization of the ΔΨm abolished P i-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented ΔΨm hyperpolarization, superoxide generation, and cytotoxicity caused by P i. High P i also promoted the opening of the mitochondrial permeability transition (PT) pore, leading to apoptosis, which was also prevented by butylmalonate. The mitochondrial antioxidants mitoTEMPO or MnTBAP prevented P i-triggered PT pore opening and cytotoxicity. Elevated extracellular P i diminished ATP synthesis, cytosolic Ca2+ oscillations, and insulin content and secretion in INS-1E cells as well as in dispersed islet cells. These parameters were restored following preincubation with mitochondrial antioxidants. This treatment also prevented high-P i-induced phosphorylation of ER stress proteins. We propose that elevated extracellular P i causes mitochondrial oxidative stress linked to mitochondrial hyperpolarization. Such stress results in reduced insulin content and defective insulin secretion and cytotoxicity. Our data explain the decreased insulin content and secretion observed under hyperphosphatemic states.

scholarly journals Melatonin Attenuates Ischemia/Reperfusion-Induced Oxidative Stress by Activating Mitochondrial Fusion in Cardiomyocytes

2022 ◽  
Vol 2022 ◽  
pp. 1-8
Author(s):  
Xiaoling Ma ◽  
Shengchi Wang ◽  
Hui Cheng ◽  
Haichun Ouyang ◽  
Xiaoning Ma
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Permeability Transition ◽  
Troponin T ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Redox Balance ◽  
Mitochondrial Fusion ◽  
Dependent Manner ◽  
Mitochondrial Oxidative Stress

Myocardial ischemia/reperfusion (I/R) injury can stimulate mitochondrial reactive oxygen species production. Optic atrophy 1- (OPA1-) induced mitochondrial fusion is an endogenous antioxidative mechanism that preserves the mitochondrial function. In our study, we investigated whether melatonin augments OPA1-dependent mitochondrial fusion and thus maintains redox balance during myocardial I/R injury. In hypoxia/reoxygenation- (H/R-) treated H9C2 cardiomyocytes, melatonin treatment upregulated OPA1 mRNA and protein expression, thereby enhancing mitochondrial fusion. Melatonin also suppressed apoptosis in H/R-treated cardiomyocytes, as evidenced by increased cell viability, diminished caspase-3 activity, and reduced Troponin T secretion; however, silencing OPA1 abolished these effects. H/R treatment augmented mitochondrial ROS production and repressed antioxidative molecule levels, while melatonin reversed these changes in an OPA1-dependent manner. Melatonin also inhibited mitochondrial permeability transition pore opening and maintained the mitochondrial membrane potential, but OPA1 silencing prevented these outcomes. These results illustrate that melatonin administration alleviates cardiomyocyte I/R injury by activating OPA1-induced mitochondrial fusion and inhibiting mitochondrial oxidative stress.

Mitochondrial oxidative stress and permeability transition in Isoniazid and Rifampicin induced liver injury in mice

2006 ◽  
Vol 45 (1) ◽  
pp. 117-126 ◽  
Author(s):  
Abhijit Chowdhury ◽  
Amal Santra ◽  
Koutilya Bhattacharjee ◽  
Subhadip Ghatak ◽  
Dhira Rani Saha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Permeability Transition ◽  
Mitochondrial Oxidative Stress

scholarly journals Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: beneficial effects of chronic exercise

2011 ◽  
Vol 301 (5) ◽  
pp. R1250-R1258 ◽  
Author(s):  
Kyle S. McCommis ◽  
Allison M. McGee ◽  
M. Harold Laughlin ◽  
Douglas K. Bowles ◽  
Christopher P. Baines
Keyword(s):  
Oxidative Stress ◽  
Exercise Training ◽  
Manganese Superoxide Dismutase ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Ros Generation ◽  
Cardiac Mitochondria ◽  
Chronic Exercise ◽  
Cyclophilin D ◽  
Mitochondrial Oxidative Stress

Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria. We tested the hypothesis that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response and that exercise training could reverse this phenotype. MPT was assessed by mitochondrial swelling in response to 10–100 μM Ca2+. FH pigs did show an increased MPT response to Ca2+ that was associated with decreases in the expression of the putative MPT pore components mitochondrial phosphate carrier (PiC) and cyclophilin-D (CypD). FH also caused increased oxidative stress, depicted by increased protein nitrotyrosylation, as well as decreased levels of reduced GSH in cardiac mitochondria. Expression of the mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD), thioredoxin-2 (Trx2), and peroxiredoxin-3 (Prx3) was greatly reduced in the FH pigs. In contrast, cytosolic catalase expression and activity were increased. However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce mitochondrial oxidative stress, and return MnSOD, Trx2, Prx3, and catalase expression/activities to normal. We conclude that FH reduces mitochondrial antioxidants, increases mitochondrial oxidative stress, and enhances the MPT response in the porcine myocardium, and that exercise training can reverse these detrimental alterations.

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