scholarly journals The Composite of 3, 4-Dihydroxyl-Phenyl Lactic Acid and Notoginsenoside R1 Attenuates Myocardial Ischemia and Reperfusion Injury Through Regulating Mitochondrial Respiratory Chain

2021 ◽  
Vol 12 ◽  
Author(s):  
Li Yan ◽  
Chun-Shui Pan ◽  
Yu-Ying Liu ◽  
Yuan-Chen Cui ◽  
Bai-He Hu ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Respiratory Chain ◽  
Complex I ◽  
Heart Function ◽  
Myocardial Infarct ◽  
Mitochondrial Respiratory Chain ◽  
Ischemia And Reperfusion ◽  
Mitochondrial Complex ◽  
Potent Effect ◽  
Myocardial Fiber

Aim3,4-Dihydroxyl-phenyl lactic acid (DLA) and notoginsenoside R1 (R1) are known to protect ischemia and reperfusion (I/R) injury by targeting Sirtuin1/NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10/the Mitochondrial Complex I (Sirt-1/NDUFA10/Complex I) and Rho-associated kinase/adenosine triphosphate (ROCK/ATP) ATP synthase δ subunit (ATP 5D), respectively. We hypothesized that a composite of the two may exhibit a more potent effect on I/R injury. The study was designed to test this hypothesis.Materials and MethodsMale Sprague–Dawley rats underwent left anterior descending artery occlusion and reperfusion, with or without DLA, R1, or a combination of 3,4-dihydroxyl-phenyl lactic acid and notoginsenoside R1 (DR) pretreatment. Heart function, myocardial morphology, myocardial infarct, myocardial blood flow (MBF), apoptosis, vascular diameter, and red blood cell (RBC) velocity in venules were evaluated. Myeloperoxidase (MPO), malondialdehyde (MDA), and 8-oxo-deoxyguanosine (8-OHdG) were assessed. The content of ATP, adenosine diphosphate (ADP), and adenosine monophosphate (AMP), the activity of mitochondrial respiratory chain Complex I and its subunit NDUFA10, the Mitochondrial Complex V (Complex V) and its subunit ATP 5D, Sirt-1, Ras homolog gene family, member A (RhoA), ROCK-1, and phosphorylated myosin light chain (P-MLC) were evaluated. R1 binding to Sirt-1 was determined by surface plasmon resonance.ResultsDLA inhibited the expression of Sirt-1, the reduction in Complex I activity and its subunit NDUFA10 expression, the increase in MPO, MDA, and 8-OhdG, and apoptosis. R1 inhibited the increase in the expression of RhoA/ROCK-1/P-MLC, the reduction of Complex V activity and its subunit ATP 5D expression, alleviated F-actin, and myocardial fiber rupture. Both DLA and R1 reduced the myocardial infarction size, increased the velocities of RBC in venules, and improved MBF and heart function impaired by I/R. DR exhibited effects similar to what was exerted, respectively, by DLA and R1 in terms of respiratory chain complexes and related signaling and outcomes, and an even more potent effect on myocardial infarct size, RBC velocity, heart function, and MBF than DLA and R1 alone.ConclusionA combination of 3,4-dihydroxyl-phenyl lactic acid and notoginsenoside R1 revealed a more potent effect on I/R injury via the additive effect of DLA and R1, which inhibited not only apoptosis caused by low expression of Sirt-1/NDUFA10/Complex I but also myocardial fiber fracture caused by RhoA/ROCK-1 activation and decreased expression of ATP/ATP 5D/Complex V.

scholarly journals Inhibition of Mitochondrial Complex I Impairs Release of α-Galactosidase by Jurkat Cells

2019 ◽  
Vol 20 (18) ◽  
pp. 4349
Author(s):  
Jonathan Lambert ◽  
Steven Howe ◽  
Ahad Rahim ◽  
Derek Burke ◽  
Simon Heales
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Jurkat Cells ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Mitochondrial Respiratory Chain Activity ◽  
Respiratory Chain Activity ◽  
Mitochondrial Respiratory

Fabry disease (FD) is caused by mutations in the GLA gene that encodes lysosomal α-galactosidase-A (α-gal-A). A number of pathogenic mechanisms have been proposed and these include loss of mitochondrial respiratory chain activity. For FD, gene therapy is beginning to be applied as a treatment. In view of the loss of mitochondrial function reported in FD, we have considered here the impact of loss of mitochondrial respiratory chain activity on the ability of a GLA lentiviral vector to increase cellular α-gal-A activity and participate in cross correction. Jurkat cells were used in this study and were exposed to increasing viral copies. Intracellular and extracellular enzyme activities were then determined; this in the presence or absence of the mitochondrial complex I inhibitor, rotenone. The ability of cells to take up released enzyme was also evaluated. Increasing transgene copies was associated with increasing intracellular α-gal-A activity but this was associated with an increase in Km. Release of enzyme and cellular uptake was also demonstrated. However, in the presence of rotenone, enzyme release was inhibited by 37%. Excessive enzyme generation may result in a protein with inferior kinetic properties and a background of compromised mitochondrial function may impair the cross correction process.

scholarly journals Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

2021 ◽  
Author(s):  
Caroline Trumpff ◽  
Edward Owusu-Ansah ◽  
Hans-Ulrich Klein ◽  
Annie Lee ◽  
Vladislav Petyuk ◽  
...  
Keyword(s):  
Human Brain ◽  
Respiratory Chain ◽  
Complex I ◽  
Molecular Mechanisms ◽  
Nuclear Dna ◽  
Mitochondrial Protein ◽  
Mitochondrial Respiratory Chain ◽  
Mtdna Copy Number ◽  
Mt Dna ◽  
Mitochondrial Respiratory

Mitochondrial respiratory chain (RC) function requires the stochiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

Abstract 476: Attenuated Activities of Mitochondria in Vascular Endothelial Cells Exposed to Oxidized or Glycated Low Density Lipoprotein

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Garry X Shen ◽  
Subir K Roy Chowdhury
Keyword(s):  
Endothelial Cells ◽  
Respiratory Chain ◽  
Complex I ◽  
Vascular Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mitochondrial Respiratory Chain ◽  
Low Density ◽  
Vascular Endothelial ◽  
Glycated Ldl

Hyperglycemia and dyslipoproteinemia are two major biochemical markers of diabetes. Elevated low density lipoprotein (LDL) is a classical risk factor for atherosclerotic cardiovascular disease. Our previous studies demonstrated that oxidized LDL (ox-LDL) and glycated LDL (gly-LDL) increased the generation of reactive oxygen species (ROS) in vascular endothelial cells. ROS is implicated in endothelial dysfunction and diabetic vascular complications. Mitochondria are an important source of ROS in the body. We hypothesize that ox-LDL or gly-LDL might affect the activity of mitochondrial respiratory chain. We evaluated the activities of mitochondrial respiratory chain complexes in porcine aortic endothelial cells (PAEC) using OROBORS oxygraph. The oxygraph was used as a highly sensitive tool to evaluate mitochondrial complex activity in freshly harvested and digitonin-permeabilized PAEC (for Complex I, the rotenone-sensitive oxidation of glutamate + malate in the presence of ADP; Complex II, antimycin A-sensitive oxidation of succinate; Complex IV, potassium cyanide-sensitive oxidation of ascorbate + TMPD). The oxygen consumption in Complex I, II and IV of PAEC was significantly decreased by >12 h of incubation with LDL, ox-LDL or gly-LDL compared to control cultures. Attenuated activity of succinate cytochrome C reductase was detected in EC treated with LDL, ox-LDL or gly-LDL for 24 h. Decreased levels of respiratory control ratio were detected in EC treated with LDL or ox-LDL for 6 h, but not for 2 h, compared to control. Impaired activity of mitochondrial complexes can cause electron leakage in the respiratory chain and substantially increase ROS formation. The findings suggest that oxidized or glycated LDL attenuates mitochondrial activities in vascular EC, which may contribute to increased ROS generation and endothelial dysfunction induced by the atherogenic lipoproteins (supported by operating grants from Canadian Institute of Health Research and Canadian Diabetes Association).

Uniparental isodisomy as a cause of mitochondrial complex I respiratory chain disorder due to a novel splicing NDUFS4 mutation

2020 ◽  
Vol 131 (3) ◽  
pp. 341-348
Author(s):  
Adrián González-Quintana ◽  
María J. Trujillo-Tiebas ◽  
Ana L. Fernández-Perrone ◽  
Alberto Blázquez ◽  
Alejandro Lucia ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Uniparental Isodisomy

scholarly journals Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)

2018 ◽  
Vol 399 (11) ◽  
pp. 1249-1264 ◽  
Author(s):  
Tomoko Ohnishi ◽  
S. Tsuyoshi Ohnishi ◽  
John C. Salerno
Keyword(s):  
Electron Transfer ◽  
Respiratory Chain ◽  
Complex I ◽  
Proton Translocation ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Proton Pumping ◽  
Entry Site ◽  
Quinone Oxidoreductase ◽  
Terminal Electron Acceptor

AbstractNADH-quinone oxidoreductase (complex I) is the largest and most complicated enzyme complex of the mitochondrial respiratory chain. It is the entry site into the respiratory chain for most of the reducing equivalents generated during metabolism, coupling electron transfer from NADH to quinone to proton translocation, which in turn drives ATP synthesis. Dysfunction of complex I is associated with neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and it is proposed to be involved in aging. Complex I has one non-covalently bound FMN, eight to 10 iron-sulfur clusters, and protein-associated quinone molecules as electron transport components. Electron paramagnetic resonance (EPR) has previously been the most informative technique, especially in membranein situanalysis. The structure of complex 1 has now been resolved from a number of species, but the mechanisms by which electron transfer is coupled to transmembrane proton pumping remains unresolved. Ubiquinone-10, the terminal electron acceptor of complex I, is detectable by EPR in its one electron reduced, semiquinone (SQ) state. In the aerobic steady state of respiration the semi-ubiquinone anion has been observed and studied in detail. Two distinct protein-associated fast and slow relaxing, SQ signals have been resolved which were designated SQNfand SQNs. This review covers a five decade personal journey through the field leading to a focus on the unresolved questions of the role of the SQ radicals and their possible part in proton pumping.

scholarly journals Mitochondrial respiratory chain super-complex I–III in physiology and pathology

2010 ◽  
Vol 1797 ◽  
pp. 9
Author(s):  
Giorgio Lenaz ◽  
Alessandra Baracca ◽  
Giovanna Barbero ◽  
Christian Bergamini ◽  
Maria Elena Dalmonte ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Respiratory
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