scholarly journals Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

2013 ◽  
Vol 20 (3) ◽  
pp. 371-381 ◽  
Author(s):  
Ségolène Hescot ◽  
Abdelhamid Slama ◽  
Anne Lombès ◽  
Angelo Paci ◽  
Hervé Remy ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Nuclear Dna ◽  
Maximum Velocity ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Dependent Manner ◽  
Respiratory Chain Complexes ◽  
Adrenocortical Cells ◽  
Native Page ◽  
Respiratory Chain Defect

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.

scholarly journals Effect of inhibitors of mitochondrial respiratory chain complexes on the electromechanical activity in human myocardium

Medicina ◽  
2010 ◽  
Vol 46 (10) ◽  
pp. 679
Author(s):  
Vida Gendvilienė ◽  
Irma Martišienė ◽  
Danguolė Zablockaitė ◽  
Jonas Jurevičius
Keyword(s):  
Respiratory Chain ◽  
Control Level ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Human Myocardium ◽  
Contraction Force ◽  
Respiratory Chain Complexes ◽  
Complex Iv ◽  
Resting Tension ◽  
Chain Complexes

The aim of the study was to investigate the effect of inhibitors of mitochondrial respiratory chain complexes I, III, and IV on the electromechanical activity in human myocardium. Material and methods. The experiments were performed on the human myocardial strips obtained from patients with heart failure (NYHA class III or IV) using a conventional method of registration of myocardial electromechanical activity. Under the perfusion with physiological Tyrode solution (control), contraction force (P) was 0.94±0.12 mN (n=16), relaxation time (t50) was 173.38±5.03 ms (n=15), action potential durations measured at 50% (AP50) and 90% (AP90) repolarization were 248.96±13.38 ms and 398.59±17.93 ms, respectively (n=13). Results. The inhibition of respiratory chain complex I by rotenone (3×10–5 M, the highest concentration applied) decreased contraction force of human myocardium to 48.99%±14.74% (n=3) (P<0.05); AP50, to 81.34%±15.81%; and AP90, to 87.28%±7.25% (n=3) (P>0.05) of control level, while relaxation time and resting tension remained almost unchanged. Antimycin A, an inhibitor of complex III, applied at the highest concentration (3×10–4 M) reduced P to 41.66%±8.8% (n=5) (P<0.001) and marginally increased t50 and decreased the durations of AP. Anoxia (3 mM Na2S2O4) that inhibits the activity of complex IV reduced the contraction force to 9.23%±3.56% (n=6) (P<0.001), AP50 and AP90 to 65.46%±9.95% and 71.07%±8.39% (n=5) (P<0.05) of control level, respectively; furthermore, the resting tension augmented (contracture developed). Conclusions. Our results show that the inhibition of respiratory chain complex IV had the strongest inhibitory effect on the electromechanical activity of failing human myocardium.

scholarly journals Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1

2020 ◽  
Vol 8 ◽  
Author(s):  
Chunhua Jiang ◽  
Balaji T. Moorthy ◽  
Devang M. Patel ◽  
Akhilesh Kumar ◽  
William M. Morgan ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Underlying Mechanism ◽  
Metabolic Effects ◽  
Respiratory Chain Complexes ◽  
Mitochondrial Respiratory Chain Complex ◽  
Human Disorders ◽  
And Function ◽  
Alpha Proteobacteria

Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the regulation of metabolism and apoptosis. Although mitochondria play relevant roles in these processes in health and disease, a causal relationship between ATE1 activity and mitochondrial biology has yet to be established. Here, we report a phylogenetic analysis that traces the roots of ATE1 to alpha-proteobacteria, the mitochondrion microbial ancestor. We then demonstrate that a small fraction of ATE1 localizes within mitochondria. Furthermore, the absence of ATE1 influences the levels, organization, and function of respiratory chain complexes in mouse cells. Specifically, ATE1-KO mouse embryonic fibroblasts have increased levels of respiratory supercomplexes I+III2+IVn. However, they have decreased mitochondrial respiration owing to severely lowered complex II levels, which leads to accumulation of succinate and downstream metabolic effects. Taken together, our findings establish a novel pathway for mitochondrial function regulation that might explain ATE1-dependent effects in various disease conditions, including cancer and aging, in which metabolic shifts are part of the pathogenic or deleterious underlying mechanism.

scholarly journals Mitochondrial myopathy caused by arsenic trioxide therapy

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4272-4274 ◽  
Author(s):  
Andoni Echaniz-Laguna ◽  
Aurélien Benoilid ◽  
Stéphane Vinzio ◽  
Luc-Matthieu Fornecker ◽  
Béatrice Lannes ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Respiratory Chain ◽  
Mitochondrial Myopathy ◽  
Lipid Droplets ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Muscle Disease ◽  
Arsenic Content ◽  
Respiratory Chain Complexes ◽  
Mtdna Deletions

Abstract Arsenic trioxide (ATO) has been successfully used as a treatment for acute promyelocytic leukemia (APL) for more than a decade. Here we report a patient with APL who developed a mitochondrial myopathy after treatment with ATO. Three months after ATO therapy withdrawal, the patient was unable to walk without assistance and skeletal muscle studies showed a myopathy with abundant cytoplasmic lipid droplets, decreased activities of the mitochondrial respiratory chain complexes, multiple mitochondrial DNA (mtDNA) deletions, and increased muscle arsenic content. Six months after ATO treatment was interrupted, the patient recovered normal strength, lipid droplets had decreased in size and number, respiratory chain complex activities were partially restored, but multiple mtDNA deletions and increased muscle arsenic content persisted. ATO therapy may provoke a delayed, severe, and partially reversible mitochondrial myopathy, and a long-term careful surveillance for muscle disease should be instituted when ATO is used in patients with APL.

scholarly journals Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

2017 ◽  
Vol 38 (1) ◽  
Author(s):  
Kewei Xie ◽  
Mingli Zhu ◽  
Peng Xiang ◽  
Xiaohuan Chen ◽  
Ayijiaken Kasimumali ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Peroxisome Proliferator ◽  
Respiratory Chain Complexes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kinase A ◽  
Mitochondrial Respiratory

ABSTRACT Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Here we show that the PKA agonist 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate–cyclic AMP (pCPT-cAMP) prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNA interference (RNAi). The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein, in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-α and ND3 promoters, suggesting that these promoters are CREB targets. In vivo, both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT-1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

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.

Relationships between the activity of respiratory-chain complexes in pre- (biopsy) or post-slaughter muscle samples and feed efficiency in random-bred Ghezel lambs

2017 ◽  
Vol 57 (8) ◽  
pp. 1674
Author(s):  
M. J. Zamiri ◽  
R. Mehrabi ◽  
G. R. Kavoosi ◽  
H. Rajaei Sharifabadi
Keyword(s):  
Respiratory Chain ◽  
Feed Intake ◽  
Enzyme Activities ◽  
Feed Efficiency ◽  
Average Daily Gain ◽  
Chain Complex ◽  
Respiratory Chain Complex ◽  
Respiratory Chain Complexes ◽  
Chain Complexes ◽  
Daily Gain

The present study was conducted to determine the relationship between the activity of mitochondrial respiratory chain complexes in pre- and post-slaughter muscle samples and residual feed intake (RFI) in Ghezel male lambs born as a result of random mating. The study was based on the hypothesis that random-bred lambs with lower feed (or higher) RFI have lower (or higher) respiratory chain-complex activity in muscle samples. Lambs (n = 30) were fed a diet consisting of 70% concentrate and 30% alfalfa hay during a 70-day period. Individual feed intake and average daily gain were recorded to calculate the RFI, feed-conversion ratio (FCR) and adjusted FCR (aFCR). On the basis of these calculations, the lambs were classified into low and high groups for RFI, with FCR and aFCR (n = 22) being one standard deviation above or below the means; this was corroborated by Student’s t-test (P &lt; 0.01). At the end of the experiment, a 10-g biopsy sample was taken from the posterior side of the left femoral biceps. After 24 h, the lambs were slaughtered, and a sample from the posterior side of the right femoral biceps was dissected for determination of mitochondrial protein and respiratory chain-complex activities (Complexes I–V). The RFI was not correlated with the metabolic bodyweight and average daily gain, but was positively correlated (r = 0.56) with the average daily feed intake (P &lt; 0.01); mean daily feed intake in the low-RFI group was 200 g less than that in the high-RFI group. The FCR and aFCR were not significantly (P &gt; 0.05) correlated with average daily feed intake (r = 0.39 and r = 0.36 respectively), but showed a negative correlation (P &lt; 0.01) with average daily gain (r = –0.73 and r = –0.76 respectively). Although very high negative correlations were recorded between the activities of all five respiratory-chain complexes and RFI in muscle samples obtained before (–0.91 to –0.97) and after (–0.92 to –0.97) slaughter, Complexes I and V showed small negative correlations (–0.40) with FCR or aFCR (P &lt; 0.05). Enzyme activities of the respiratory-chain Complexes I, III and V were not significantly different between the pre- and post-slaughter biopsy samples; however, the enzyme activities of respiratory-chain Complexes II and IV were slightly higher in post-slaughter samples (P &lt; 0.01). These results suggested that it may be possible to use the enzymatic activity of respiratory-chain complexes in muscle biopsy samples for screening of lambs for RFI, providing a useful procedure for genetic selection of lambs for this component of feed efficiency. These encouraging results need to be verified in further experiments using other sheep breeds and a larger number of lambs.

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