Mitochondrial functional impairment in response to environmental toxins in the cardiorenal metabolic syndrome

Jia, Guanghong; Aroor, Annayya R.; Martinez‐Lemus, Luis A.; Sowers, James R.

doi:10.1007/s00204-014-1431-3

Cited by 34 publications

(13 citation statements)

References 56 publications

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“…Mitochondria dysfunction is one of the major cellular sources of reactive oxygen species (ROS) during ischaemia–reperfusion (I/R) . Increased production of ROS further exacerbates the impairment of mitochondrial DNA and results in cell apoptosis . Mitochondrial damage‐mediated cardiomyocyte apoptosis plays a pivotal role in myocardial I/R injury .…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial PKC‐ε deficiency promotes I/R‐mediated myocardial injury via GSK3β‐dependent mitochondrial permeability transition pore opening

Wang

Zhang

Zhao

et al. 2017

J Cellular Molecular Medi

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Mitochondrial fission is critically involved in cardiomyocyte apoptosis, which has been considered as one of the leading causes of ischaemia/reperfusion (I/R)‐induced myocardial injury. In our previous works, we demonstrate that aldehyde dehydrogenase‐2 (ALDH2) deficiency aggravates cardiomyocyte apoptosis and cardiac dysfunction. The aim of this study was to elucidate whether ALDH2 deficiency promotes mitochondrial injury and cardiomyocyte death in response to I/R stress and the underlying mechanism. I/R injury was induced by aortic cross‐clamping for 45 min. followed by unclamping for 24 hrs in ALDH2 knockout (ALDH2−/−) and wild‐type (WT) mice. Then myocardial infarct size, cell apoptosis and cardiac function were examined. The protein kinase C (PKC) isoform expressions and their mitochondrial translocation, the activity of dynamin‐related protein 1 (Drp1), caspase9 and caspase3 were determined by Western blot. The effects of N‐acetylcysteine (NAC) or PKC‐δ shRNA treatment on glycogen synthase kinase‐3β (GSK‐3β) activity and mitochondrial permeability transition pore (mPTP) opening were also detected. The results showed that ALDH2−/− mice exhibited increased myocardial infarct size and cardiomyocyte apoptosis, enhanced levels of cleaved caspase9, caspase3 and phosphorylated Drp1. Mitochondrial PKC‐ε translocation was lower in ALDH2−/− mice than in WT mice, and PKC‐δ was the opposite. Further data showed that mitochondrial PKC isoform ratio was regulated by cellular reactive oxygen species (ROS) level, which could be reversed by NAC pre‐treatment under I/R injury. In addition, PKC‐ε inhibition caused activation of caspase9, caspase3 and Drp1Ser616 in response to I/R stress. Importantly, expression of phosphorylated GSK‐3β (inactive form) was lower in ALDH2−/− mice than in WT mice, and both were increased by NAC pre‐treatment. I/R‐induced mitochondrial translocation of GSK‐3β was inhibited by PKC‐δ shRNA or NAC pre‐treatment. In addition, mitochondrial membrane potential (∆Ψm) was reduced in ALDH2−/− mice after I/R, which was partly reversed by the GSK‐3β inhibitor (SB216763) or PKC‐δ shRNA. Collectively, our data provide the evidence that abnormal PKC‐ε/PKC‐δ ratio promotes the activation of Drp1 signalling, caspase cascades and GSK‐3β‐dependent mPTP opening, which results in mitochondrial injury‐triggered cardiomyocyte apoptosis and myocardial dysfuction in ALDH2−/− mice following I/R stress.

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Section: Introductionmentioning

confidence: 99%

“…Increased production of ROS further exacerbates the impairment of mitochondrial DNA and results in cell apoptosis . Mitochondrial damage‐mediated cardiomyocyte apoptosis plays a pivotal role in myocardial I/R injury .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial PKC‐ε deficiency promotes I/R‐mediated myocardial injury via GSK3β‐dependent mitochondrial permeability transition pore opening

Wang

Zhang

Zhao

et al. 2017

J Cellular Molecular Medi

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“…An increase in the ANS fluorescence intensity may be attributed to the hydrophobicity of the binding site of the probe . Mercuric ions mainly act on sulfhydryl groups of mitochondrial membrane proteins, causing an altered mitochondrial permeability, which further leads to irregularities in the electron transport system . Similarly, arsenic is known to cause alterations in the mitochondrial membrane potential, and to disrupt the electron transport system, principally altering the activity of the mitochondrial complexes .…”

Section: Resultsmentioning

confidence: 99%

Detection of mitochondrial dysfunction in vitro by laser‐induced autofluorescence

Raghushaker

Chandra

Chakrabarty

et al. 2019

Journal of Biophotonics

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Mitochondrion plays a significant role in a variety of biological functions. Because of their diverse character and location in the cellular systems, mitochondria commonly get exposed to various extrinsic and intrinsic cellular stresses. The present study reports a novel approach to detection of mitochondrial dysfunction based on tryptophan autofluorescence of its proteins in mouse liver, using laser-induced fluorescence (LIF) as a tool. Mitochondria, isolated from the mouse liver, were initially tested for purity and integrity using lactate dehydrogenase and succinate dehydrogenase (SDH) assays.Mitochondrial stress was induced by treating the isolated mitochondria with heavy metals at 10 and 0.01 mM for sodium arsenite and mercuric chloride, respectively. Upon treatment with the heavy metal, tryptophan autofluorescence quenching was recorded at 281 nm excitation. The functional integrity of the mitochondria treated with heavy metals was evaluated by measuring SDH and cytochrome c oxidase activities at various concentrations of mitochondria, which showed impaired activity as compared to control upto a concentration of 6.25 μg. A significant shift was also observed in the autofluorescence of proteins upto the level below 1 μg, suggesting their conformational change and hence altered structural integrity of mitochondria. Circular dichroism spectroscopy data of the mitochondrial proteins treated with heavy metals further validates their conformational change as compared to untreated control. The present study clearly shows that the LIF can be a novel detection tool to detect altered structural integrity of cellular mitochondria upon stress, and it also possesses the potentiality to combine with other interdisciplinary modalities. K E Y W O R D SANS fluorescence, heavy metals, LDH and SDH assay, tryptophan autofluorescence

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“…Permeabilization of the outer membrane by BAX/BAK activates apoptosis through the release of proapoptotic proteins, such as cytochrome c, apoptosis-inducing factor, SMAC/DIABLO, and endonuclease G (49,60). Although this leads to apoptosis, opening of the mPTP causes collapse of the proton gradient, resulting in massive influx of solutes and water into the mitochondrial matrix (48). This leads to swelling of the inner membrane and rupture of the outer membrane, causing necrosis (48).…”

Section: Apoptosismentioning

confidence: 99%

MicroRNAs as regulators of mitochondrial dysfunction and obesity

Murri

Azzouzi

2018

American Journal of Physiology-Heart and Circulatory Physiology

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Obesity, which has become a major global epidemic, is associated with numerous comorbidities and nearly every chronic condition. Mitochondria play a central role in this disorder, as they control cell metabolism, regulating important processes, such as ATP production, lipid β-oxidation, oxidative stress, and inflammation. MicroRNAs (miRs) have been shown to regulate many biological processes associated with obesity, comprising adipocyte differentiation, insulin action, and fat metabolism. In addition, recent studies have confirmed that miRs are important regulators of mitochondrial function by either directly modulating mitochondrial proteins or targeting mitochondrial regulators, thereby modulating metabolic process in the context of obesity. In this review, we describe the different roles of mitochondria in obesity, specifically in adipose tissue, and those miRs that are involved in mitochondrial dysfunction in this disease.

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Mitochondrial functional impairment in response to environmental toxins in the cardiorenal metabolic syndrome

Cited by 34 publications

References 56 publications

Mitochondrial PKC‐ε deficiency promotes I/R‐mediated myocardial injury via GSK3β‐dependent mitochondrial permeability transition pore opening

Mitochondrial PKC‐ε deficiency promotes I/R‐mediated myocardial injury via GSK3β‐dependent mitochondrial permeability transition pore opening

Detection of mitochondrial dysfunction in vitro by laser‐induced autofluorescence

MicroRNAs as regulators of mitochondrial dysfunction and obesity

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