scholarly journals Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1202 ◽  
Author(s):  
Wiersma ◽  
van Marion ◽  
Wüst ◽  
Houtkooper ◽  
Zhang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Model Systems ◽  
Mitochondrial Stress ◽  
Atp Production ◽  
Calcium Uniporter ◽  
Pathophysiological Role ◽  
Experimental Model Systems ◽  
Partial Blocking

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target.

scholarly journals Dicalcium silicate-induced mitochondrial dysfunction and autophagy-mediated macrophagic inflammation promotes osteogenic differentiation of BMSCs

2021 ◽  
Author(s):  
Qianting Luo ◽  
Xingyang Li ◽  
Wenchao Zhong ◽  
Wei Cao ◽  
Mingjing Zhu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Osteogenic Differentiation ◽  
Mitochondrial Function ◽  
Macrophage Polarization ◽  
Vital Role ◽  
Dicalcium Silicate ◽  
Osteogenic Potential ◽  
Mitochondrial Morphology ◽  
Mouse Bone Marrow ◽  
Atp Production

Abstract Dicalcium silicate (Ca2SiO4, C2S) has osteogenic potential but induces macrophagic inflammation. Mitochondrial function plays a vital role in macrophage polarization and macrophagic inflammation. The mitochondrial function of C2S-treated macrophages is still unclear. This study hypothesized: (1) the C2S modulates mitochondrial function and autophagy in macrophages to regulate macrophagic inflammation, and (2) C2S-induced macrophagic inflammation regulates osteogenesis. We used RAW264.7 cells as a model of macrophage. The C2S (75-150 μg/mL) extract was used to analyze the macrophagic mitochondrial function and macrophage-mediated effect on osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (BMSCs). The results showed that C2S extract (150 μg/mL) induced TNF-α, IL-1β, and IL-6 production in macrophages. C2S extract (150 μg/mL) enhanced reactive oxygen species (ROS) level and intracellular calcium level but reduced mitochondrial membrane potential (MtMP) and ATP production. TEM images showed reduced mitochondrial abundance and altered the mitochondrial morphology in C2S (150 μg/mL)-treated macrophages. Protein level expression of PINK1, Parkin, Beclin1, and LC3 was upregulated but TOMM20 was downregulated. mRNA sequencing and KEGG analysis showed that C2S-induced differentially expressed mRNAs in macrophages were mainly distributed in the essential signaling pathways involved in mitochondrial function and autophagy. The conditioned medium from C2S-treated macrophage (C2S-CM) robustly promoted osteogenic differentiation in BMSCs. In conclusion, our results indicate mitochondrial dysfunction and autophagy as the possible mechanism of C2S-induced macrophagic inflammation. The promotion of osteogenic differentiation of BMSCs by the C2S-induced macrophagic inflammation suggests the potential application of C2S in developing immunomodulatory bone grafts.

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

2009 ◽  
Vol 297 (5) ◽  
pp. R1516-R1525 ◽  
Author(s):  
Nicolas Theys ◽  
Thomas Bouckenooghe ◽  
Marie-Thérèse Ahn ◽  
Claude Remacle ◽  
Brigitte Reusens
Keyword(s):  
Mitochondrial Dysfunction ◽  
Glucose Intolerance ◽  
Mitochondrial Function ◽  
Uncoupling Protein ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Fetal Life ◽  
Atp Production ◽  
Low Protein ◽  
Specific Manner

Mitochondrial dysfunction may be a long-term consequence of a poor nutritional environment during early life. Our aim was to investigate whether a maternal low-protein (LP) diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (control) or 8% protein (LP diet) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3-mo-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared with control offspring. The expression of malate dehydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared with control. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased reactive oxygen species production associated with a higher expression of mitochondrial subunits of the electron transport chain NADH-ubiquinone oxireductase subunit 4L, an overexpression of peroxisome proliferator-activated receptor-γ and uncoupling protein-2, and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed an LP diet.

scholarly journals TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

2015 ◽  
Vol 36 (5) ◽  
pp. 2072-2082 ◽  
Author(s):  
Peng Zhang ◽  
Yong Lu ◽  
Dong Yu ◽  
Dadong Zhang ◽  
Wei Hu
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Complex Activity ◽  
Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

scholarly journals DIMT1, a regulator of ribosomal biogenesis, controls β-cell protein synthesis, mitochondrial function and insulin secretion

2020 ◽  
Author(s):  
Gaurav Verma ◽  
Alexander Bowen ◽  
Alexander Hamilton ◽  
Jonathan Esguerra ◽  
Alexandros Karagiannopoulos ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Insulin Secretion ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cell Protein ◽  
Ribosomal Biogenesis ◽  
Β Cells ◽  
Β Cell ◽  
Ribosomal Subunits ◽  
Atp Production

AbstractWe previously reported that transcription factor B1 mitochondrial (TFB1M) is involved in the pathogenesis of type 2 diabetes (T2D) owing to mitochondrial dysfunction. Here, we describe that dimethyladenosine transferase 1 homolog (DIMT1), a homologue of TFB1M, is expressed and active in pancreatic β-cells. Like TFB1M, it has been implicated in control of ribosomal RNA (rRNA) but its role in β-cells or T2D remains to be identified. Silencing of DIMT1 impacted mitochondrial function, leading to reduced expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate (OCR), dissipated mitochondrial membrane potential (ΔΨm) and caused a lower rate of ATP production (mATP). In addition, DIMT1 knockdown slowed the rate of protein synthesis. In accordance with these findings, DIMT1-deficiency perturbed insulin secretion in rodent and human β-cell lines. These effects are likely a result of destabilization of ribosomal assembly, involving NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1). These are two critical ribosomal subunits proteins, whose interactions were perturbed upon DIMT1-deficiency, thereby disturbing protein synthesis in β-cells. Thus, we have here highlighted a role of DIMT1 in ribosomal biogenesis that perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both being potential pathogenetic factors in T2D.

scholarly journals Protective Role ofPsoralea corylifoliaL. Seed Extract against Hepatic Mitochondrial Dysfunction Induced by Oxidative Stress or Aging

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Eunhui Seo ◽  
Yoon Sin Oh ◽  
Donghee Kim ◽  
Mi-Young Lee ◽  
Sungwook Chae ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Hepg2 Cells ◽  
Peroxisome Proliferator ◽  
Ros Production ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Production ◽  
Genome Damage

The accumulation of oxidative damage and mitochondrial dysfunction is an important factor that contributes to aging. ThePsoralea corylifoliaseeds (PCS), commonly known as “Boh-Gol-Zhee” in Korea, have been used traditionally as a medicinal remedy. We investigated whether an extract of PCS has protective effects on oxidative stress and mitochondrial function in hepatocytes. The PCS extract showed an antisenescence effect on human diploid fibroblasts as evidenced by a decreased expression ofp16INK4amRNA and senescence-associatedβ-galactosidase staining. PCS extract treatment reduced H2O2-induced reactive oxygen species (ROS) production in HepG2 cells, inhibited ROS production in hepatocytes of aged mice, and increased superoxide dismutase activity. In H2O2-treated HepG2 cells, PCS extract treatment recovered ATP production. PCS extract treatment recovered the oxygen consumption rate and inhibited reduction of mitochondrial membrane potential induced by oxidative stress, suggesting improvement of mitochondrial function. In addition, PCS extract treatment recovered peroxisome proliferator-activated receptorγcoactivator 1αand carnitine palmitoyltransferase 1 mRNA and protein expression, and inhibited mitochondrial genome damage. Treatment with the major component of PCS extract, bakuchiol, also recovered mitochondrial dysfunction. On the basis of these results, we conclude that PCS extract inhibits ROS production and mitochondrial dysfunction induced by oxidative stress in hepatocytes.

scholarly journals Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells

2006 ◽  
Vol 291 (4) ◽  
pp. F840-F855 ◽  
Author(s):  
Grażyna Nowak ◽  
Ginger L. Clifton ◽  
Malinda L. Godwin ◽  
Diana Bakajsova
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Complex I ◽  
Protective Effects ◽  
Atp Production ◽  
Aconitase Activity ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Pathway Inhibition ◽  
Complex I Activity

Previously, we showed that oxidant exposure in renal proximal tubular cells (RPTC) induces mitochondrial dysfunction mediated by PKC-ε. This study examined the role of ERK1/2 in mitochondrial dysfunction induced by oxidant injury and whether PKC-ε mediates its effects on mitochondrial function through the Raf-MEK1/2-ERK1/2 pathway. Sublethal injury produced by tert-butylhydroperoxide (TBHP) resulted in three- to fivefold increase in phosphorylation of ERK1/2 and p38 but not JNK. This was followed by decreases in basal and uncoupled respirations (41%), state 3 respiration and ATP production coupled to complex I (46%), and complex I activity (42%). Oxidant exposure decreased aconitase activity 30% but not pyruvate, α-ketoglutarate, and malate dehydrogenase activities. Inhibition of ERK1/2 restored basal and state 3 respirations, ΔΨm, ATP production, and complex I activity but not aconitase activity. In contrast, activation of ERK1/2 by expression of constitutively active MEK1 suppressed basal, uncoupled, and state 3 respirations in noninjured RPTC to the levels observed in TBHP-injured RPTC. MEK1/2 inhibition did not change Akt or p38 phosphorylation, demonstrating that the protective effect of MEK1/2 inhibitor was not due to activation of Akt or inhibition of p38 pathway. Inhibition of PKC-ε did not block TBHP-induced ERK1/2 phosphorylation in whole RPTC or in mitochondria. We conclude that 1) oxidant-induced activation of ERK1/2 but not p38 or JNK reduces mitochondrial respiration and ATP production by decreasing complex I activity and substrate oxidation through complex I, 2) citric acid cycle dehydrogenases are not under control of the ERK1/2 pathway in oxidant-injured RPTC, 3) the protective effects of ERK1/2 inhibition are not due to activation of Akt, and 4) ERK1/2 and PKC-ε mediate oxidant-induced mitochondrial dysfunction through independent pathways.

scholarly journals Phytochemicals from Cocoa Shell Protect Mitochondrial Function and Alleviate Oxidative Stress in Hepatocytes via Regulation of ERK and PI3K-AKT Pathways

2021 ◽  
Vol 2 (1) ◽  
pp. 25
Author(s):  
Miguel Rebollo-Hernanz ◽  
Yolanda Aguilera ◽  
Maria A. Martin-Cabrejas ◽  
Elvira Gonzalez de Mejia
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Aqueous Extract ◽  
Mitochondrial Function ◽  
Nonalcoholic Fatty Liver ◽  
Atp Production ◽  
Mitochondrial Superoxide ◽  
Cocoa Shell ◽  
The Impact

This research aimed to assess the impact of an aqueous extract from the cocoa shell and its major phytochemicals on preventing oxidative stress and mitochondrial dysfunction in hepatocytes using an in vitro model of nonalcoholic fatty liver disease (NAFLD). The phytochemicals from cocoa shell were extracted using water and characterized by UPLC-MS/MS analysis. HepG2 cells were cotreated with either the aqueous extract from cocoa shell (CAE, 20–100 µg mL−1) or 10–50 µmol L−1 of pure theobromine, protocatechuic acid, procyanidin B2, epicatechin, and catechin in the presence or absence of palmitic acid (PA, 500 µmol L−1) to mimic NAFLD conditions in vitro. Biomarkers of mitochondrial function and oxidative stress were evaluated 24 h after the cotreatment in cell supernatants and lysates using chemical, biochemical, and immunochemical techniques. CAE and the phytochemicals therein significantly (p < 0.05) protected mitochondrial content (15–100%) and preserved mitochondrial function, promoting O2 consumption (1.2- to 1.8-fold) and ATP production (1.3- to 2.1-fold). Phytochemicals from cocoa shell significantly (p < 0.05) decreased PA-triggered oxidative stress. The mitochondrial membrane potential was maintained (62–100%), and the production of mitochondrial superoxide (26–100%) and total ROS (17–100%) was abrogated. CAE significantly (p < 0.05) modulated cell signaling pathways associated with ROS production and mitochondrial dysfunction, including an increase in the phosphorylation of ERK1/2 (2.8-fold), protein kinase B (AKT) (2.8-fold), GSK3 (2.3-fold), Raf-1 (1.9-fold), and mTOR (1.7-fold). In conclusion, results suggested that the cocoa shell’s phytochemicals could protect mitochondrial liver function and alleviate oxidative stress by modulating key pathways involved in their regulation.

scholarly journals Glycine ameliorates mitochondrial dysfunction caused by ABT-199 in porcine oocytes

2021 ◽  
Author(s):  
Sicong Yu ◽  
Lepeng Gao ◽  
Yang Song ◽  
Xin Ma ◽  
Shuang Liang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Oocyte Maturation ◽  
Mitochondrial Function ◽  
Protective Action ◽  
Damage Model ◽  
Developmental Competence ◽  
Free Calcium ◽  
Maturation In Vitro

Abstract Mitochondria play an important role in controlling oocyte developmental competence. Our previous studies showed that glycine can regulate mitochondrial function and improve oocyte maturation in vitro. However, the mechanisms by which glycine affects mitochondrial function during oocyte maturation in vitro have not been fully investigated. In this study, we induced a mitochondrial damage model in oocytes with the Bcl-2-specific antagonist ABT-199. We investigated whether glycine could reverse the mitochondrial dysfunction induced by ABT-199 exposure and whether it is related to calcium regulation. Our results showed that ABT-199 inhibited cumulus expansion, decreased the oocyte maturation rate and the intracellular glutathione (GSH) level, caused mitochondrial dysfunction, induced oxidative stress, which was confirmed by decreased mitochondrial membrane potential (Δ⍦m) and the expression of mitochondrial function-related genes (PGC-1α), and increased reactive oxygen species (ROS) levels and the expression of apoptosis-associated genes (Bax, caspase-3, CytC). More importantly, ABT-199-treated oocytes showed an increase in the intracellular free calcium concentration ([Ca 2+]i) and had impaired cortical type 1 inositol 1,4,5-trisphosphate receptors (IP3R1) distribution. Nevertheless, treatment with glycine significantly ameliorated mitochondrial dysfunction, oxidative stress and apoptosis, glycine also regulated [Ca 2+]i levels and IP3R1 cellular distribution, which further protects oocyte maturation in ABT-199-induced porcine oocytes. Taken together, our results indicate that glycine has a protective action against ABT-199-induced mitochondrial dysfunction in porcine oocytes.

scholarly journals Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 609
Author(s):  
Nunzia Mollo ◽  
Matteo Esposito ◽  
Miriam Aurilia ◽  
Roberta Scognamiglio ◽  
Rossella Accarino ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mitochondrial Dysfunction ◽  
Neuronal Differentiation ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Atp Synthesis ◽  
Differentiation Markers ◽  
Differentiation Potential ◽  
Atp Production ◽  
Mitochondrial Alterations

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

scholarly journals Regulation of Cytochrome c Oxidase by Natural Compounds Resveratrol, (–)-Epicatechin, and Betaine

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1346
Author(s):  
Icksoo Lee
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Model Systems ◽  
Health Improvement ◽  
Published Data ◽  
Mitochondrial Electron Transport Chain ◽  
Naturally Occurring ◽  
Transport Chain ◽  
Wide Range ◽  
Experimental Model Systems

Numerous naturally occurring molecules have been studied for their beneficial health effects. Many compounds have received considerable attention for their potential medical uses. Among them, several substances have been found to improve mitochondrial function. This review focuses on resveratrol, (–)-epicatechin, and betaine and summarizes the published data pertaining to their effects on cytochrome c oxidase (COX) which is the terminal enzyme of the mitochondrial electron transport chain and is considered to play an important role in the regulation of mitochondrial respiration. In a variety of experimental model systems, these compounds have been shown to improve mitochondrial biogenesis in addition to increased COX amount and/or its enzymatic activity. Given that they are inexpensive, safe in a wide range of concentrations, and effectively improve mitochondrial and COX function, these compounds could be attractive enough for possible therapeutic or health improvement strategies.

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