scholarly journals DJ-1 attenuates the glycation of mitochondrial complex I and complex III in the post-ischemic heart

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yvanna Pantner ◽  
Rohini Polavarapu ◽  
Lih-Shen Chin ◽  
Lian Li ◽  
Yuuki Shimizu ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Complex I ◽  
Ischemia Reperfusion ◽  
Active Form ◽  
Atp Synthesis ◽  
Complex Iii ◽  
Ischemic Heart ◽  
Atp Production ◽  
Myocardial Ischemia Reperfusion ◽  
Complex Activities

AbstractDJ-1 is a ubiquitously expressed protein that protects cells from stress through its conversion into an active protease. Recent work found that the active form of DJ-1 was induced in the ischemic heart as an endogenous mechanism to attenuate glycative stress—the non-enzymatic glycosylation of proteins. However, specific proteins protected from glycative stress by DJ-1 are not known. Given that mitochondrial electron transport proteins have a propensity for being targets of glycative stress, we investigated if DJ-1 regulates the glycation of Complex I and Complex III after myocardial ischemia–reperfusion (I/R) injury. Initial studies found that DJ-1 localized to the mitochondria and increased its interaction with Complex I and Complex III 3 days after the onset of myocardial I/R injury. Next, we investigated the role DJ-1 plays in modulating glycative stress in the mitochondria. Analysis revealed that compared to wild-type control mice, mitochondria from DJ-1 deficient (DJ-1 KO) hearts showed increased levels of glycative stress following I/R. Additionally, Complex I and Complex III glycation were found to be at higher levels in DJ-1 KO hearts. This corresponded with reduced complex activities, as well as reduced mitochondrial oxygen consumption ant ATP synthesis in the presence of pyruvate and malate. To further determine if DJ-1 influenced the glycation of the complexes, an adenoviral approach was used to over-express the active form of DJ-1(AAV9-DJ1ΔC). Under I/R conditions, the glycation of Complex I and Complex III were attenuated in hearts treated with AAV9-DJ1ΔC. This was accompanied by improvements in complex activities, oxygen consumption, and ATP production. Together, this data suggests that cardiac DJ-1 maintains Complex I and Complex III efficiency and mitochondrial function during the recovery from I/R injury. In elucidating a specific mechanism for DJ-1’s role in the post-ischemic heart, these data break new ground for potential therapeutic strategies using DJ-1 as a target.

Abstract 355: Effect of Poloxamer 188 on Rat Brain Isolated Mitochondria After Exposure to Hydrogen Peroxide

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Johannes A Pille ◽  
Michele M Salzman ◽  
Anna A Sonju ◽  
Felicia P Lotze ◽  
Josephine E Hees ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Oxygen Consumption ◽  
Mitochondrial Function ◽  
Complex I ◽  
Room Temperature ◽  
In Vitro Model ◽  
Atp Synthesis ◽  
Complex Ii ◽  
Vitro Model

Introduction: In a pig model of myocardial infarction (MI), intracoronary delivered Poloxamer (P) 188 significantly reduces ischemia/reperfusion (IR) injury when given immediately upon reperfusion, with improved mitochondrial function as a predominant effect. As mitochondria are heavily damaged during IR, a direct effect of P188 on mitochondria may lead to better therapy options during reperfusion. To show not only a similar reduction of IR injury by P188 in the brain, but also a direct P188 effect on mitochondria, we established an in-vitro model of IR that consists of damaging isolated rat brain mitochondria with hydrogen peroxide (H 2 O 2 ), one component of ischemia, then applying P188, and analyzing mitochondrial function. Methods: Male Sprague-Dawley rat brains were removed, and the mitochondria isolated by differential centrifugation and Percoll gradients, then kept on ice to slow their bioenergetics prior to any experimental treatments. Mitochondria were exposed to 200 μM H 2 O 2 for 10 min at room temperature with slight agitation; controls received no H 2 O 2 . Samples were then diluted ½ with buffer ± P188 (250 μM after dilution) to simulate reperfusion and treatment, and kept at room temperature for 10 further minutes. ATP synthesis was measured in a luminometer using a luciferase enzymatic assay. Oxygen consumption was measured by closed cell respirometry with an oxygen meter. In both assays, Complex I and Complex II were examined; Complex I substrates glutamate and malate, Complex II substrate succinate plus the Complex I inhibitor rotenone. Statistics: Data are expressed as mean ± SEM. One-Way ANOVA, SNK-Test; Kruskal-Wallis-Test; α=0.05, * vs control. Results: In both Complex I and II, mitochondrial function was significantly impaired by H 2 O 2 , with ATP synthesis affected more at Complex I and oxygen consumption affected more at Complex II. Addition of P188 did not provide any significant improvement in mitochondrial function. Conclusions: Although P188 significantly reduced IR injury when given during reperfusion in a pig model of MI, it does not appear to provide direct protection to mitochondria in this in-vitro model. Whether the exposure to H 2 O 2 causes the appropriate injury for P188 to become effective remains to be elucidated.

scholarly journals N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through a β-Catenin–Dependent Manner

2020 ◽  
Vol 126 (7) ◽  
pp. 857-874 ◽  
Author(s):  
Wenjun Yan ◽  
Chen Lin ◽  
Yongzhen Guo ◽  
Youhu Chen ◽  
Yunhui Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ischemia Reperfusion ◽  
Capillary Density ◽  
Ischemic Heart ◽  
Protective Effects ◽  
Ischemic Heart Failure ◽  
Cardiomyocyte Proliferation ◽  
Myocardial Ischemia Reperfusion

Rationale: Mesenchymal stromal cell–based therapy is promising against ischemic heart failure. However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently. Objective: The current study investigates whether and how N-cadherin may regulate mesenchymal stromal cells retention and cardioprotective capability against ischemic heart failure. Methods and Results: Adult mice–derived adipose tissue–derived mesenchymal stromal cells (ADSC) were transfected with adenovirus harboring N-cadherin, T-cadherin, or control adenovirus. CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion. ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was used to determine the molecular mechanisms. Compared with ADSC transfected with adenovirus-control, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC transfected with adenovirus-N-cadherin significantly preserved capillary density and increased cardiomyocyte proliferation and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC transfected with adenovirus-N-cadherin (but not ADSC transfected with adenovirus-T-cadherin) significantly increased left ventricular ejection fraction and reduced fibrosis in both MI and myocardial ischemia/reperfusion mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP (matrix metallopeptidases)-10/13 and HGF (hepatocyte growth factor) upregulation is responsible for N-cadherin’s effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/β-catenin complex formation and active β-catenin levels in the nucleus. β-catenin knockdown abolished N-cadherin overexpression–induced MMP-10, MMP-13, and HGF expression and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin. Conclusions: We demonstrate for the first time that N-cadherin overexpression enhances mesenchymal stromal cells–protective effects against ischemic heart failure via β-catenin-mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.

Generation of adenosine tri-phosphate in Leishmania donovani amastigote forms

2014 ◽  
Vol 59 (1) ◽  
Author(s):  
Subhasish Mondal ◽  
Jay Roy ◽  
Tanmoy Bera
Keyword(s):  
Cell Growth ◽  
Cell Survival ◽  
Complex I ◽  
Leishmania Donovani ◽  
Complex Iii ◽  
Low Oxygen ◽  
Atp Production ◽  
Substrate Level Phosphorylation ◽  
Metabolic Systems ◽  
Substrate Level

AbstractLeishmania, the causative agent of various forms of leishmaniasis, is the significant cause of morbidity and mortality. Regarding energy metabolism, which is an essential factor for the survival, parasites adapt to the environment under low oxygen tension in the host using metabolic systems which are very different from that of the host mammals. We carried out the study of susceptibilities to different inhibitors of mitochondrial electron transport chain and studies on substrate level phosphorylation in wild-type L. donovani. The amastigote forms of L. donovani are independent on oxidative phosphorylation for ATP production. Indeed, its cell growth was not inhibited by excess oligomycin and dicyclohexylcarbodiimide, which are the most specific inhibitors of the mitochondrial Fo/F1-ATP synthase. In contrast, mitochondrial complex I inhibitor rotenone and complex III inhibitor antimycin A inhibited amastigote cell growth, suggesting the role of complex I and complex III in cell survival. Complex II appeared to have no role in cell survival. To further investigate the site of ATP production, we studied the substrate level phosphorylation, which was involved in the synthesis of ATP. Succinate-pyruvate couple showed the highest substrate level phosphorylation in amastigotes whereas NADH-fumarate and NADH-pyruvate couples failed to produce ATP. In contrast, NADPH-fumarate showed the highest rate of ATP formation in promastigotes. Therefore, we can conclude that substrate level phosphorylation is essential for the survival of amastigote forms of Leishmania donovani.

Exosomes: promising sacks for treating ischemic heart disease?

2017 ◽  
Vol 313 (3) ◽  
pp. H508-H523 ◽  
Author(s):  
Gui-Hao Chen ◽  
Jun Xu ◽  
Yue-Jin Yang
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Regeneration ◽  
Ischemic Heart ◽  
Advantages And Disadvantages ◽  
Developing Heart ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Ischemic heart disease(IHD) is the leading cause of death worldwide. Despite the development of continuously improving therapeutic strategies, morbidity and mortality of patients with IHD remain relatively high. Exosomes are a subpopulation of vesicles that are universally recognized as major mediators in intercellular communication. Numerous preclinical studies have shown that these tiny vesicles were protective in IHD, through such actions as alleviating myocardial ischemia-reperfusion injury, promoting angiogenesis, inhibiting fibrosis, and facilitating cardiac regeneration. Our review focused on these beneficial exosome-mediated processes. In addition, we discuss in detail how to fully exploit the therapeutic potentials of exosomes in the field of IHD. Topics include identifying robust sources of exosomes, loading protective agents into exosomes, developing heart-specific exosomes, optimizing isolation methods, and translating the cardioprotective effects of exosomes into clinical practice. Finally, both the advantages and disadvantages of utilizing exosomes in clinical settings are addressed.

scholarly journals Higd1a is a positive regulator of cytochrome c oxidase

2015 ◽  
Vol 112 (5) ◽  
pp. 1553-1558 ◽  
Author(s):  
Takaharu Hayashi ◽  
Yoshihiro Asano ◽  
Yasunori Shintani ◽  
Hiroshi Aoyama ◽  
Hidetaka Kioka ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Structural Changes ◽  
Regulatory Mechanism ◽  
Atp Synthesis ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Domain Family ◽  
Raman Analysis ◽  
Atp Production ◽  
Positive Regulator ◽  
Inducible Genes

Cytochrome c oxidase (CcO) is the only enzyme that uses oxygen to produce a proton gradient for ATP production during mitochondrial oxidative phosphorylation. Although CcO activity increases in response to hypoxia, the underlying regulatory mechanism remains elusive. By screening for hypoxia-inducible genes in cardiomyocytes, we identified hypoxia inducible domain family, member 1A (Higd1a) as a positive regulator of CcO. Recombinant Higd1a directly integrated into highly purified CcO and increased its activity. Resonance Raman analysis revealed that Higd1a caused structural changes around heme a, the active center that drives the proton pump. Using a mitochondria-targeted ATP biosensor, we showed that knockdown of endogenous Higd1a reduced oxygen consumption and subsequent mitochondrial ATP synthesis, leading to increased cell death in response to hypoxia; all of these phenotypes were rescued by exogenous Higd1a. These results suggest that Higd1a is a previously unidentified regulatory component of CcO, and represents a therapeutic target for diseases associated with reduced CcO activity.

Effects of L-propionylcarnitine on mechanical recovery during reflow in intact hearts

1988 ◽  
Vol 255 (1) ◽  
pp. H169-H176 ◽  
Author(s):  
A. J. Liedtke ◽  
L. DeMaison ◽  
S. H. Nellis
Keyword(s):  
Fatty Acids ◽  
Oxygen Consumption ◽  
Fatty Acid ◽  
Myocardial Oxygen Consumption ◽  
Ischemia Reperfusion ◽  
Acid Oxidation ◽  
Clinical Use ◽  
New Treatment ◽  
Myocardial Ischemia Reperfusion ◽  
Mechanical Recovery

We tested the influence of L-propionylcarnitine (LPC) in modifying mechanical stunning during reflow. Nineteen adolescent anesthetized swine were extracorporeally perfused at control coronary flows for 20 min, supplemented with excess fatty acids (average values 1.1 +/- 0.1 mumol/ml), and subjected to 45 min regional ischemia (-60 delta % decrease in anterior descending flow) followed by 35 min reperfusion. Responses in 10 placebo hearts were compared with those obtained from 9 animals treated with 50 mg/kg LPC at 0 min perfusion and 40 mg/kg at 40 min perfusion. Ischemia in placebo hearts caused a 62.6 delta % decrease in active shortening in anterior descending bed, which failed to recover (-41.4 delta % from control values) during reflow. Conversely, in LPC-treated hearts, decreases in active shortening (-38.6 and -11.6 delta %) during ischemia and reflow, respectively, were significantly smaller (P less than or equal to 0.05). This improved motion was associated with greater rates of myocardial oxygen consumption but similar levels of fatty acid oxidation and fatty acid intermediates. Thus LPC significantly reversed mechanical stunning in myocardial ischemia/reperfusion protocols, presumably because of its positive inotropic properties. This derivative, otherwise innocuous in nature, could represent an attractive new treatment choice for future clinical use.

Modeling the effects of hypoxia on ATP turnover in exercising muscle

1992 ◽  
Vol 73 (2) ◽  
pp. 737-742 ◽  
Author(s):  
P. G. Arthur ◽  
M. C. Hogan ◽  
D. E. Bebout ◽  
P. D. Wagner ◽  
P. W. Hochachka
Keyword(s):  
Oxygen Consumption ◽  
Metabolic Control ◽  
Lactate Production ◽  
Atp Synthesis ◽  
Atp Production ◽  
Atp Turnover ◽  
Model Based ◽  
The Face ◽  
Energetic State ◽  
Atp Supply

Most models of metabolic control concentrate on the regulation of ATP production and largely ignore the regulation of ATP demand. We describe a model, based on the results of Hogan et al. (J. Appl. Physiol. 73: 728–736, 1992), that incorporates the effects of ATP demand. The model is developed from the premise that a unique set of intracellular conditions can be measured at each level of ATP turnover and that this relationship is best described by energetic state. Current concepts suggest that cells are capable of maintaining oxygen consumption in the face of declines in the concentration of oxygen through compensatory changes in cellular metabolites. We show that these compensatory changes can cause significant declines in ATP demand and result in a decline in oxygen consumption and ATP turnover. Furthermore we find that hypoxia does not directly affect the rate of anaerobic ATP synthesis and associated lactate production. Rather, lactate production appears to be related to energetic state, whatever the PO2. The model is used to describe the interaction between ATP demand and ATP supply in determining final ATP turnover.

scholarly journals Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3

2017 ◽  
Vol 114 (45) ◽  
pp. 11908-11913 ◽  
Author(s):  
Hengxun Hu ◽  
Jinliang Nan ◽  
Yong Sun ◽  
Dan Zhu ◽  
Changchen Xiao ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Oxygen Consumption ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Cell Protection ◽  
Causative Relationship ◽  
R Process ◽  
And Function

The causative relationship between specific mitochondrial molecular structure and reactive oxygen species (ROS) generation has attracted much attention. NDUFA13 is a newly identified accessory subunit of mitochondria complex I with a unique molecular structure and a location that is very close to the subunits of complex I of low electrochemical potentials. It has been reported that down-regulated NDUFA13 rendered tumor cells more resistant to apoptosis. Thus, this molecule might provide an ideal opportunity for us to investigate the profile of ROS generation and its role in cell protection against apoptosis. In the present study, we generated cardiac-specific tamoxifen-inducible NDUFA13 knockout mice and demonstrated that cardiac-specific heterozygous knockout (cHet) mice exhibited normal cardiac morphology and function in the basal state but were more resistant to apoptosis when exposed to ischemia-reperfusion (I/R) injury. cHet mice showed a preserved capacity of oxygen consumption rate by complex I and II, which can match the oxygen consumption driven by electron donors ofN,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD)+ascorbate. Interestingly, at basal state, cHet mice exhibited a higher H2O2level in the cytosol, but not in the mitochondria. Importantly, increased H2O2served as a second messenger and led to the STAT3 dimerization and, hence, activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the I/R process in cHet mice.

scholarly journals Mitoflash biogenesis and its role in the autoregulation of mitochondrial proton electrochemical potential

2019 ◽  
Vol 151 (6) ◽  
pp. 727-737 ◽  
Author(s):  
Gaomin Feng ◽  
Beibei Liu ◽  
Jinghang Li ◽  
Tianlei Cheng ◽  
Zhanglong Huang ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Complex I ◽  
Atp Synthesis ◽  
Electrochemical Potential ◽  
Cardiac Mitochondria ◽  
Entry Site ◽  
Complex Iv ◽  
Electron Transfer Chain ◽  
Atp Production ◽  
Transfer Chain

Respiring mitochondria undergo an intermittent electrical and chemical excitation called mitochondrial flash (mitoflash), which transiently uncouples mitochondrial respiration from ATP production. How a mitoflash is generated and what specific role it plays in bioenergetics remain incompletely understood. Here, we investigate mitoflash biogenesis in isolated cardiac mitochondria by varying the respiratory states and substrate supply and by dissecting the involvement of different electron transfer chain (ETC) complexes. We find that robust mitoflash activity occurs once mitochondria are electrochemically charged by state II/IV respiration (i.e., no ATP synthesis at Complex V), regardless of the substrate entry site (Complex I, Complex II, or Complex IV). Inhibiting forward electron transfer abolishes, while blocking reverse electron transfer generally augments, mitoflash production. Switching from state II/IV to state III respiration, to allow for ATP synthesis at Complex V, markedly diminishes mitoflash activity. Intriguingly, when mitochondria are electrochemically charged by the ATPase activity of Complex V, mitoflashes are generated independently of ETC activity. These findings suggest that mitoflash biogenesis is mechanistically linked to the build up of mitochondrial electrochemical potential rather than ETC activity alone, and may functionally counteract overcharging of the mitochondria and hence serve as an autoregulator of mitochondrial proton electrochemical potential.

scholarly journals Impact of diabetes-associated lipoproteins on oxygen consumption and mitochondrial enzymes in porcine aortic endothelial cells.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Xueping Xie ◽  
Subir Roy Chowdhury ◽  
Ganesh Sangle ◽  
Garry X Shen
Keyword(s):  
Endothelial Cells ◽  
Oxygen Consumption ◽  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Respiration ◽  
Complex I ◽  
Complex Iii ◽  
Mitochondrial Enzymes ◽  
Key Enzymes ◽  
Cytochrome C Reductase

Impairments in mitochondrial function have been proposed to play an important role in the pathogenesis of diabetes. Atherosclerotic coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Mitochondrial dysfunction and increased production of reactive oxygen species (ROS) are associated with diabetes and CAD. Elevated levels of glycated low density lipoproteins (glyLDL) and oxidized LDL (oxLDL) were detected in patients with diabetes. Our previous studies demonstrated that oxLDL and glyLDL increased the generation of ROS and altered the activities of antioxidant enzymes in vascular endothelial cells (EC). The present study examined the effects of glyLDL and oxLDL on mitochondrial respiration, membrane potential and the activities and proteins of key enzymes in mitochondrial electron transport chain (mETC) in cultured porcine aortic EC (PAEC). The results demonstrated that glyLDL or oxLDL significantly reduced oxygen consumption in Complex I, II/III and IV of mETC in PAEC compared to LDL or vehicle control using oxygraphy. Incubation with glyLDL or oxLDL significantly reduced mitochondrial membrane potential, the activities of mitochondrial ETC enzymes - NADH dehydrogenase (Complex I), succinate cytochrome c reductase (Complex II + III), ubiquinol cytochrome c reductase (Complex III), and cytochrome c oxidase (Complex IV) in PAEC compared to LDL or control. Treatment with oxLDL or glyLDL reduced the abundance of subunits of Complex I, ND1 and ND6 in PAEC. However, the effects of oxLDL on mitochondrial activity and proteins were not significantly different from glyLDL. The findings suggest that the glyLDL or oxLDL impairs mitochondrial respiration, as a result from the reduction of the abundance of several key enzymes in mitochondria of vascular EC, which potentially may lead to oxidative stress in vascular EC, and the development of diabetic vascular complications.

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