scholarly journals Using Human Primary Foreskin Fibroblasts to Study Cellular Damage and Mitochondrial Dysfunction

2020 ◽  
Vol 86 (1) ◽  
Author(s):  
Cristina A. Nadalutti ◽  
Samuel H. Wilson
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cellular Damage

scholarly journals Amelioration of Mitochondrial Quality Control and Proteostasis by Natural Compounds in Parkinson’s Disease Models

2019 ◽  
Vol 20 (20) ◽  
pp. 5208 ◽  
Author(s):  
Bongki Cho ◽  
Taeyun Kim ◽  
Yu-Jin Huh ◽  
Jaemin Lee ◽  
Yun-Il Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Ubiquitin Proteasome System ◽  
Natural Compounds ◽  
Cellular Damage ◽  
Pathophysiological Mechanism ◽  
Neuroprotective Effects ◽  
Age Related

Parkinson’s disease (PD) is a well-known age-related neurodegenerative disorder associated with longer lifespans and rapidly aging populations. The pathophysiological mechanism is a complex progress involving cellular damage such as mitochondrial dysfunction and protein homeostasis. Age-mediated degenerative neurological disorders can reduce the quality of life and also impose economic burdens. Currently, the common treatment is replacement with levodopa to address low dopamine levels; however, this does not halt the progression of PD and is associated with adverse effects, including dyskinesis. In addition, elderly patients can react negatively to treatment with synthetic neuroprotection agents. Recently, natural compounds such as phytochemicals with fewer side effects have been reported as candidate treatments of age-related neurodegenerative diseases. This review focuses on mitochondrial dysfunction, oxidative stress, hormesis, proteostasis, the ubiquitin‒proteasome system, and autophagy (mitophagy) to explain the neuroprotective effects of using natural products as a therapeutic strategy. We also summarize the efforts to use natural extracts to develop novel pharmacological candidates for treatment of age-related PD.

scholarly journals Oxidative Stress and Epilepsy: Literature Review

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Carlos Clayton Torres Aguiar ◽  
Anália Barbosa Almeida ◽  
Paulo Victor Pontes Araújo ◽  
Rita Neuma Dantas Cavalcante de Abreu ◽  
Edna Maria Camelo Chaves ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Mitochondrial Dysfunction ◽  
Experimental Studies ◽  
Cellular Damage ◽  
Brain Disorder ◽  
Chronic Oxidative Stress ◽  
Seizure Models ◽  
And Oxidative Stress

Backgrounds. The production of free radicals has a role in the regulation of biological function, cellular damage, and the pathogenesis of central nervous system conditions. Epilepsy is a highly prevalent serious brain disorder, and oxidative stress is regarded as a possible mechanism involved in epileptogenesis. Experimental studies suggest that oxidative stress is a contributing factor to the onset and evolution of epilepsy.Objective. A review was conducted to investigate the link between oxidative stress and seizures, and oxidative stress and age as risk factors for epilepsy. The role of oxidative stress in seizure induction and propagation is also discussed.Results/Conclusions. Oxidative stress and mitochondrial dysfunction are involved in neuronal death and seizures. There is evidence that suggests that antioxidant therapy may reduce lesions induced by oxidative free radicals in some animal seizure models. Studies have demonstrated that mitochondrial dysfunction is associated with chronic oxidative stress and may have an essential role in the epileptogenesis process; however, few studies have shown an established link between oxidative stress, seizures, and age.

scholarly journals Mitochondrial Dysfunction in Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-18 ◽  
Author(s):  
P. C. Keane ◽  
M. Kurzawa ◽  
P. G. Blain ◽  
C. M. Morris
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Energy Levels ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitochondrial Respiratory Chain ◽  
Cellular Damage ◽  
Substantia Nigra Pars Compacta ◽  
Transport Chain

Parkinson's disease (PD) is a progressive, neurodegenerative condition that has increasingly been linked with mitochondrial dysfunction and inhibition of the electron transport chain. This inhibition leads to the generation of reactive oxygen species and depletion of cellular energy levels, which can consequently cause cellular damage and death mediated by oxidative stress and excitotoxicity. A number of genes that have been shown to have links with inherited forms of PD encode mitochondrial proteins or proteins implicated in mitochondrial dysfunction, supporting the central involvement of mitochondria in PD. This involvement is corroborated by reports that environmental toxins that inhibit the mitochondrial respiratory chain have been shown to be associated with PD. This paper aims to illustrate the considerable body of evidence linking mitochondrial dysfunction with neuronal cell death in the substantia nigra pars compacta (SNpc) of PD patients and to highlight the important need for further research in this area.

scholarly journals Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mounir El Maï ◽  
Marta Marzullo ◽  
Inês Pimenta de Castro ◽  
Miguel Godinho Ferreira
Keyword(s):  
Mitochondrial Dysfunction ◽  
Genome Instability ◽  
Cellular Damage ◽  
Cell Fates ◽  
Telomere Shortening ◽  
Akt Activation ◽  
Compensatory Proliferation ◽  
Foxo Transcription Factors ◽  
Tissue Alterations

Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.

scholarly journals Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction

2019 ◽  
Vol 116 (37) ◽  
pp. 18435-18444 ◽  
Author(s):  
Wei Qian ◽  
Namrata Kumar ◽  
Vera Roginskaya ◽  
Elise Fouquerel ◽  
Patricia L. Opresko ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Mitochondrial Dysfunction ◽  
Nuclear Dna ◽  
Apoptotic Cell ◽  
Chain Complex ◽  
Cellular Damage ◽  
Secondary Wave ◽  
Telomere Dysfunction ◽  
Complex Activity ◽  
Strand Breaks

Reactive oxygen species (ROS) play important roles in aging, inflammation, and cancer. Mitochondria are an important source of ROS; however, the spatiotemporal ROS events underlying oxidative cellular damage from dysfunctional mitochondria remain unresolved. To this end, we have developed and validated a chemoptogenetic approach that uses a mitochondrially targeted fluorogen-activating peptide (Mito-FAP) to deliver a photosensitizer MG-2I dye exclusively to this organelle. Light-mediated activation (660 nm) of the Mito-FAP–MG-2I complex led to a rapid loss of mitochondrial respiration, decreased electron transport chain complex activity, and mitochondrial fragmentation. Importantly, one round of singlet oxygen produced a persistent secondary wave of mitochondrial superoxide and hydrogen peroxide lasting for over 48 h after the initial insult. By following ROS intermediates, we were able to detect hydrogen peroxide in the nucleus through ratiometric analysis of the oxidation of nuclear cysteine residues. Despite mitochondrial DNA (mtDNA) damage and nuclear oxidative stress induced by dysfunctional mitochondria, there was a lack of gross nuclear DNA strand breaks and apoptosis. Targeted telomere analysis revealed fragile telomeres and telomere loss as well as 53BP1-positive telomere dysfunction-induced foci (TIFs), indicating that DNA double-strand breaks occurred exclusively in telomeres as a direct consequence of mitochondrial dysfunction. These telomere defects activated ataxia-telangiectasia mutated (ATM)-mediated DNA damage repair signaling. Furthermore, ATM inhibition exacerbated the Mito-FAP–induced mitochondrial dysfunction and sensitized cells to apoptotic cell death. This profound sensitivity of telomeres through hydrogen peroxide induced by dysregulated mitochondria reveals a crucial mechanism of telomere–mitochondria communication underlying the pathophysiological role of mitochondrial ROS in human diseases.

scholarly journals THU0011 ANALYSIS OF METABOLIC STATUS IN CYBRIDS REVEALED IMPAIRED METABOLIC FLEXIBILITY IN OA PROCESS.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 217.1-218
Author(s):  
A. Dalmao-Fernandez ◽  
J. Lund ◽  
T. Hermida Gómez ◽  
M. E. Vazquez Mosquera ◽  
I. Rego-Perez ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Lipid Droplet ◽  
Mitochondrial Dynamics ◽  
Cellular Damage ◽  
Metabolic Flexibility ◽  
Special Focus ◽  
Metabolic Demand ◽  
Mitofusin 2

Background:There are several metabolic pathways involved in cell metabolism, including glycolysis, tricarboxylic acid (TCA) cycle and fatty acid (FA) oxidation. Metabolic flexibility has previously described as the ability to respond or adapt to changes in metabolic demand; assessed by the ability to switch from fat to carbohydrate oxidation. In the last years there is a growing interest to assess the influence of metabolic flexibility, as a mechanism to explain how lipids can accumulate in the tissue. During OA, it has been established a relationship between mitochondrial dysfunction and cellular damage due to impairments in mitochondrial function and metabolic flexibility. Several studies have suggested that fatty acids may play an important role in OA development and progression.Objectives:The aim of this work was to examine the differences in glucose and fatty acid metabolism, with special focus on metabolic flexibility, in cybrids from healthy (N) or OA donors.Methods:Cybrids were developed using 143B.TK-Rho-0 cell line (nuclear donor) and platelets (mitochondrial donors) from healthy (N) and OA donors. Glucose and FA metabolism were measured using D-[14C(U)]glucose and [1-14C]oleic acid respectively. Metabolic flexibility was evaluated by co-culturing with glucose and oleic acid acutely by using inhibitors against glucose and FA oxidation, 20µM UK5099 and 10µM etomoxir, respectively. Incorporation of FA into lipid droplet (LD) was evaluated by thin layer chromatography and LD were stained by LD540 and analyzed by confocal microscope and flow cytometry. Mitochondrial dynamics was measured by real-time PCR method. Percentage of mitochondrial Anion Superoxide (O2-) production was evaluated incubating cells with MitoSox® using Flow Cytometer. Appropriate statistical analyses were performed with GraphPad Prism v6.Results:There were no changes in basal glucose metabolism between cybrids. N cybrids had higher acid-soluble metabolites, reflecting incomplete FA β-oxidation than OA cybrids. Comparing glucose and FA metabolism showed that both types of cybrids preferred to oxidize glucose. Co-culturing with glucose and Oleic acid, increased total cellular uptake and oxidation of glucose in N compared to basal condition (Figure-1) and in this condition the OA cybrids showed an increase in mitochondrial O2-production. Inhibition of FA oxidation by etomoxir increased complete glucose oxidation of N cybrids but not in OA cybrids that had a preference to oxidize oleic acid compared to basal condition. Gene expression of mitofusin-2 (MFN2) was higher in N than OA cybrids under inhibiting conditions. Combine these data indicate that N cybrids are more metabolically flexible and have better adaptative response than OA. Cybrids presented different lipid distribution patterns. Lipid droplet (LD) formation increased in both groups incubated in presence of FA. Furthermore, N cybrids showed less LD formation than OA.Conclusion:The results indicated that cybrids from OA patients had reduced metabolic flexibility compared to N cybrids. These results enhance our understanding of the mitochondria metabolism in OA, suggesting a mitochondrial dysfunction and impairment of metabolic flexibility during the OA process.Disclosure of Interests:Andrea Dalmao-Fernandez: None declared, Jenny Lund: None declared, Tamara Hermida Gómez: None declared, Maria Eugenia Vazquez Mosquera: None declared, Ignacio Rego-Perez: None declared, Francisco J. Blanco Grant/research support from: Sanofi-Aventis, Lilly, Bristol MS, Amgen, Pfizer, Abbvie, TRB Chemedica International, Glaxo SmithKline, Archigen Biotech Limited, Novartis, Nichi-iko pharmaceutical Co, Genentech, Jannsen Research & Development, UCB Biopharma, Centrexion Theurapeutics, Celgene, Roche, Regeneron Pharmaceuticals Inc, Biohope, Corbus Pharmaceutical, Tedec Meiji Pharma, Kiniksa Pharmaceuticals, Ltd, Gilead Sciences Inc, Consultant of: Lilly, Bristol MS, Pfizer, Mercedes Fernandez-Moreno: None declared

scholarly journals DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy

2021 ◽  
Vol 22 (11) ◽  
pp. 5675
Author(s):  
Jinglong Chen ◽  
Danping Wang ◽  
Yibo Zong ◽  
Xiaojing Yang
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Liver Diseases ◽  
Antioxidant Effect ◽  
Cellular Damage ◽  
Autophagic Flux

Oxidative stress occurs in a variety of clinical liver diseases and causes cellular damage and mitochondrial dysfunction. The clearance of damaged mitochondria by mitophagy may facilitate mitochondrial biogenesis and enhance cell survival. Although the supplementation of docosahexaenoic acid (DHA) has been recognized to relieve the symptoms of various liver diseases, the antioxidant effect of DHA in liver disease is still unclear. The purpose of our research was to investigate the antioxidant effect of DHA in the liver and the possible role of mitophagy in this. In vitro, H2O2-induced injury was caused in AML12 cells. The results showed that DHA repressed the level of reactive oxygen species (ROS) induced by H2O2 and stimulated the cellular antioxidation response. Most notably, DHA restored oxidative stress-impaired autophagic flux and promoted protective autophagy. In addition, PINK/Parkin-mediated mitophagy was activated by DHA in AML12 cells and alleviated mitochondrial dysfunction. The ERK1/2 signaling pathway was inhibited during oxidative stress but reactivated by DHA treatment. It was proven that the expression of ERK1/2 was involved in the regulation of mitophagy by the ERK1/2 inhibitor. We further proved these results in vivo. DHA effectively alleviated the liver oxidative damage caused by CCl4 and enhanced antioxidation capacity; intriguingly, autophagy was also activated. In summary, our data demonstrated that DHA protected hepatocytes from oxidative damage through GPR120/ERK-mediated mitophagy.

Leukotoxin, 9,10-epoxy-12-octadecenoate inhibits mitochondrial respiration of isolated perfused rat lung

1995 ◽  
Vol 269 (3) ◽  
pp. L326-L331 ◽  
Author(s):  
T. Sakai ◽  
T. Ishizaki ◽  
T. Ohnishi ◽  
F. Sasaki ◽  
S. Ameshima ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Ex Vivo ◽  
Direct Action ◽  
Significant Inhibition ◽  
Cellular Damage ◽  
Lung Edema ◽  
Rat Lung ◽  
Mitochondrial Uncoupling ◽  
Wet Weight

To investigate how mitochondrial function was affected in leukotoxin (Lx)-,9,10-epoxy-12-octadecenoate-induced lung injury, lung mitochondria were extracted from isolated perfused rat lung with or without Lx-induced edematous injury. In the lung treated with 30 mumol of Lx, the mitochondrial respiration rate in states 3 and 4 significantly decreased (without mitochondrial uncoupling) concomitantly with increased release of lactate dehydrogenase (LDH), a parameter for cellular damage, into the perfusate and decreased ATP content in the lung tissue compared with those of untreated lung. Moreover, 30 mumol of Lx resulted in significant inhibition of cytochrome-c oxidase activity (vs. vehicle control). In contrast, lower doses of Lx (10 mumol) caused lung edema and cellular damage without evidence for mitochondrial dysfunction. We also examined cellular and mitochondrial damage in hydrostatic lung edema. Such edema showed neither suppressed mitochondrial respiration nor elevated LDH activity in perfusate, although lung wet weight increased as much as it did after 30 mumol Lx treatment. Our results suggest that the ex vivo mitochondrial dysfunction is one of the secondary (vs. initial augmented permeability) but specific manifestations of toxicity of Lx, and together with the previous reports, the ex vivo damaging effect of Lx against mitochondria may be ascribed not to its direct action on mitochondria but to Lx-derived cellular mechanism(s).

scholarly journals Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase–silent mating type information regulation 2 homologue 1–PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine

2014 ◽  
Vol 113 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Lei Bao ◽  
Xiaxia Cai ◽  
Zhaofeng Zhang ◽  
Yong Li
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Dysfunction ◽  
Mating Type ◽  
Mesangial Cells ◽  
Grape Seed ◽  
Cellular Damage ◽  
Terminal Deoxynucleotidyl Transferase ◽  
High Dose ◽  
Amp Activated Protein Kinase ◽  
Type Information

Grape seed procyanidin B2 (GSPB2), an antioxidative and anti-inflammatory polyphenol in grape seed, has been found to have protective effects on diabetic nephropathy. Based on its favourable biological activities, in the present study, we aimed to investigate whether GSPB2 could inhibit apoptosis in rat mesangial cells treated with glucosamine (GlcN) under high-dose conditions. The results showed that the administration of GSPB2 (10 μg/ml) significantly increased the viability of mesangial cells treated with GlcN at a dose of 15 mm. We found that GSPB2 inhibited apoptosis in mesangial cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphates (dUTP) nick-end labelling staining and flow cytometry technique (P< 0·05 for both). GSPB2 treatment also suppressed oxidative stress by elevating the activity of glutathione peroxidase (P< 0·05) and superoxide dismutase (P< 0·01), as well as prevented cellular damage. GSPB2 enhanced the mRNA expression of nuclear respiratory factor 1, mitochondrial transcription factor A and mitochondrial DNA copy number in mesangial cells as determined by real-time PCR (P< 0·05 for each). Finally, GSPB2 treatment activated the protein expression of PPARγ co-activator-1α (PGC-1α), silent mating type information regulation 2 homologue 1 (SIRT1) and AMP-activated protein kinase (AMPK) in mesangial cells. These findings suggest that GSPB2 markedly ameliorates mitochondrial dysfunction and inhibits apoptosis in rat mesangial cells treated with high-dose GlcN. This protective effect could be, at least in part, due to the activation of the AMPK–SIRT1–PGC-1α axis.

scholarly journals The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes

2021 ◽  
Vol 8 ◽  
Author(s):  
Olga A. Zhunina ◽  
Nikita G. Yabbarov ◽  
Andrey V. Grechko ◽  
Antonina V. Starodubova ◽  
Ekaterina Ivanova ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Protein ◽  
Cellular Damage ◽  
Future Perspective ◽  
Antioxidant Systems ◽  
Mtdna Damage ◽  
Mtdna Mutations ◽  
Wide Range

Mitochondrial dysfunction is known to be associated with a wide range of human pathologies, such as cancer, metabolic, and cardiovascular diseases. One of the possible ways of mitochondrial involvement in the cellular damage is excessive production of reactive oxygen and nitrogen species (ROS and RNS) that cannot be effectively neutralized by existing antioxidant systems. In mitochondria, ROS and RNS can contribute to protein and mitochondrial DNA (mtDNA) damage causing failure of enzymatic chains and mutations that can impair mitochondrial function. These processes further lead to abnormal cell signaling, premature cell senescence, initiation of inflammation, and apoptosis. Recent studies have identified numerous mtDNA mutations associated with different human pathologies. Some of them result in imbalanced oxidative phosphorylation, while others affect mitochondrial protein synthesis. In this review, we discuss the role of mtDNA mutations in cancer, diabetes, cardiovascular diseases, and atherosclerosis. We provide a list of currently described mtDNA mutations associated with each pathology and discuss the possible future perspective of the research.

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