scholarly journals Hypoxia Promotes Mitochondrial Complex I Abundance via HIF-1α in Complex III and Complex IV Deficient Cells

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2197
Author(s):  
Amy Saldana-Caboverde ◽  
Nadee Nissanka ◽  
Sofia Garcia ◽  
Anne Lombès ◽  
Francisca Diaz
Keyword(s):  
Complex I ◽  
De Novo ◽  
Genetic Defect ◽  
Pleiotropic Effect ◽  
Complex Iii ◽  
Low Oxygen ◽  
Respiratory Complexes ◽  
Hypoxia Exposure ◽  
Hypoxic Conditions ◽  
Rieske Iron Sulfur Protein

Murine fibroblasts deficient in mitochondria respiratory complexes III (CIII) and IV (CIV) produced by either the ablation of Uqcrfs1 (encoding for Rieske iron sulfur protein, RISP) or Cox10 (encoding for protoheme IX farnesyltransferase, COX10) genes, respectively, showed a pleiotropic effect in complex I (CI). Exposure to 1–5% oxygen increased the levels of CI in both RISP and COX10 KO fibroblasts. De novo assembly of the respiratory complexes occurred at a faster rate and to higher levels in 1% oxygen compared to normoxia in both RISP and COX10 KO fibroblasts. Hypoxia did not affect the levels of assembly of CIII in the COX10 KO fibroblasts nor abrogated the genetic defect impairing CIV assembly. Mitochondrial signaling involving reactive oxygen species (ROS) has been implicated as necessary for HIF-1α stabilization in hypoxia. We did not observe increased ROS production in hypoxia. Exposure to low oxygen levels stabilized HIF-1α and increased CI levels in RISP and COX10 KO fibroblasts. Knockdown of HIF-1α during hypoxic conditions abrogated the beneficial effect of hypoxia on the stability/assembly of CI. These findings demonstrate that oxygen and HIF-1α regulate the assembly of respiratory complexes.

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.

scholarly journals Increased supraorganization of respiratory complexes is a dynamic multistep remodelling in response to proteostasis stress

2020 ◽  
Vol 133 (18) ◽  
pp. jcs248492
Author(s):  
Shivali Rawat ◽  
Suparna Ghosh ◽  
Debodyuti Mondal ◽  
Valpadashi Anusha ◽  
Swasti Raychaudhuri
Keyword(s):  
Complex I ◽  
Protein Complexes ◽  
Mitochondrial Protein ◽  
Complex Iii ◽  
Complex Iv ◽  
Mitochondrial Proteome ◽  
Respiratory Complexes ◽  
The Core ◽  
Mitochondrial Functions ◽  
Folding Pathways

ABSTRACTProteasome-mediated degradation of misfolded proteins prevents aggregation inside and outside mitochondria. But how do cells safeguard the mitochondrial proteome and mitochondrial functions despite increased aggregation during proteasome inactivation? Here, using a novel two-dimensional complexome profiling strategy, we report increased supraorganization of respiratory complexes (RCs) in proteasome-inhibited cells that occurs simultaneously with increased pelletable aggregation of RC subunits inside mitochondria. Complex II (CII) and complex V (CV) subunits are increasingly incorporated into oligomers. Complex I (CI), complex III (CIII) and complex IV (CIV) subunits are engaged in supercomplex formation. We unravel unique quinary states of supercomplexes during early proteostatic stress that exhibit plasticity and inequivalence of constituent RCs. The core stoichiometry of CI and CIII is preserved, whereas the composition of CIV varies. These partially disintegrated supercomplexes remain functionally competent via conformational optimization. Subsequently, increased stepwise integration of RC subunits into holocomplexes and supercomplexes re-establishes steady-state stoichiometry. Overall, the mechanism of increased supraorganization of RCs mimics the cooperative unfolding and folding pathways for protein folding, but is restricted to RCs and is not observed for any other mitochondrial protein complexes.This article has an associated First Person interview with the first author of the paper.

scholarly journals Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2809
Author(s):  
Paolo Uva ◽  
Maria Carla Bosco ◽  
Alessandra Eva ◽  
Massimo Conte ◽  
Alberto Garaventa ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Mtor Inhibitors ◽  
Gene Set Enrichment Analysis ◽  
Low Oxygen ◽  
Connectivity Map ◽  
Hypoxic Conditions ◽  
Connectivity Score

Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis.

scholarly journals Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations

2015 ◽  
Vol 172 (6) ◽  
pp. 803-811 ◽  
Author(s):  
Maya B Lodish ◽  
Bo Yuan ◽  
Isaac Levy ◽  
Glenn D Braunstein ◽  
Charalampos Lyssikatos ◽  
...  
Keyword(s):  
Copy Number ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Genetic Defect ◽  
Molecular Cytogenetics ◽  
Case Series ◽  
Sporadic Case ◽  
Genomic Rearrangements ◽  
Clinical Presentations ◽  
Depth Analysis

ObjectiveWe have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype–phenotype correlation of theirPRKACAamplification.DesignThis study is a case series.MethodsMolecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.ResultsReinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entirePRKACAgene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient,PRKACAtriplication was associated with a more severe phenotype.ConclusionsConstitutional chromosomalPRKACAgene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occurde novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication.PRKACAamplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

scholarly journals The idebenone metabolite QS10 is an electron donor to complex III and rescues respiration in complex I-deficient cells and rotenone-treated zebrafish

2016 ◽  
Vol 1857 ◽  
pp. e50-e51
Author(s):  
Marco Schiavone ◽  
Valentina Giorgio ◽  
Valeria Petronilli ◽  
Francesco Argenton ◽  
Tatiana Da Ros ◽  
...  
Keyword(s):  
Electron Donor ◽  
Complex I ◽  
Complex Iii

scholarly journals Long-Term Waterlogging as Factor Contributing to Hypoxia Stress Tolerance Enhancement in Cucumber: Comparative Transcriptome Analysis of Waterlogging Sensitive and Tolerant Accessions

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 189
Author(s):  
Kinga Kęska ◽  
Michał Wojciech Szcześniak ◽  
Izabela Makałowska ◽  
Małgorzata Czernicka
Keyword(s):  
Stress Tolerance ◽  
De Novo ◽  
Average Length ◽  
Marker Genes ◽  
Long Term Memory ◽  
Low Oxygen ◽  
Waterlogging Tolerance ◽  
Pre Treatment ◽  
Waterlogging Treatment

Waterlogging (WL), excess water in the soil, is a phenomenon often occurring during plant cultivation causing low oxygen levels (hypoxia) in the soil. The aim of this study was to identify candidate genes involved in long-term waterlogging tolerance in cucumber using RNA sequencing. Here, we also determined how waterlogging pre-treatment (priming) influenced long-term memory in WL tolerant (WL-T) and WL sensitive (WL-S) i.e., DH2 and DH4 accessions, respectively. This work uncovered various differentially expressed genes (DEGs) activated in the long-term recovery in both accessions. De novo assembly generated 36,712 transcripts with an average length of 2236 bp. The results revealed that long-term waterlogging had divergent impacts on gene expression in WL-T DH2 and WL-S DH4 cucumber accessions: after 7 days of waterlogging, more DEGs in comparison to control conditions were identified in WL-S DH4 (8927) than in WL-T DH2 (5957). Additionally, 11,619 and 5007 DEGs were identified after a second waterlogging treatment in the WL-S and WL-T accessions, respectively. We identified genes associated with WL in cucumber that were especially related to enhanced glycolysis, adventitious roots development, and amino acid metabolism. qRT-PCR assay for hypoxia marker genes i.e., alcohol dehydrogenase (adh), 1-aminocyclopropane-1-carboxylate oxidase (aco) and long chain acyl-CoA synthetase 6 (lacs6) confirmed differences in response to waterlogging stress between sensitive and tolerant cucumbers and effectiveness of priming to enhance stress tolerance.

Abstract 269: 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) Decreases Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) and Attenuates Endoplasmic Reticulum Stress in Rat Placental Villi Explants

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Christopher T Banek ◽  
Haley E Gillham ◽  
Sarah M Johnson ◽  
Hans C Dreyer ◽  
Jeffrey S Gilbert
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
De Novo ◽  
Vegf Receptor ◽  
Sprague Dawley ◽  
Hypoxic Conditions ◽  
Ampk Phosphorylation ◽  
Angiogenic Balance ◽  
Placental Villi ◽  
Placental Ischemia

Preeclampsia, defined by the onset of de novo hypertension and proteinuria near the 20th week of gestation, is a major contributor to maternal and fetal morbidity and mortality worldwide. Preeclampsia is often preceded by placental ischemia and an imbalance in circulating angiogenic factors (e.g. VEGF - vascular endothelial growth factor, sFlt-1 - soluble VEGF receptor 1). Recent studies also report increased expression of endoplasmic reticulum (ER) stress products in preeclamptic placentas. Our laboratory recently reported 5-aminoimidazole-4-carboxamide-3-ribonuceloside (AICAR) reduces blood pressure and improves angiogenic balance (increased VEGF, decreased sFlt-1) in rats with placental ischemia-induced hypertension, but the mechanism is unclear. We hypothesized AICAR would decrease sFlt-1, increase AMPK phosphorylation, and decrease ER stress in hypoxic placental villous explants. On day 19 of pregnancy, placentas were isolated from four Sprague-Dawley rats and immediately dissected in ice-cold phosphate-buffered saline. Explants were cultured for 12 hours in physiologic normoxic (8% O2) and hypoxic (1.5% O2) conditions. All experiments were performed in triplicate. VEGF secretion was unaffected by AICAR treatment in both normoxic and hypoxic conditions. AICAR decreased sFlt -1 secretion in hypoxic villi (2147±116 vs. *1411±67, P<0.05). Additionally, AMPK activation ratio was increased with AICAR, and was hypoxic-dependent (8%: 2.9±0.3; 8%+A: 3.3±0.1; 1.5%: 3.5±0.1; 1.5%+A: *4.5±0.01;*P<.05). Moreover, markers of ER stress were increased with hypoxia, and decreased with AICAR treatment (BiP 8%: 1.2±0.2; 8%+A: 1.0±0.0; 1.5%: *8.3±0.7; 1.5%+A: 1.9±0.0.3;*P<.05), (CHOP 8%: 0.5±0.0; 8%+A: 0.3±0.1; 1.5%: *1.7±0.1; 1.5%+A: 0.7±0.1;*P<.05). ATF4 was not changed with hypoxia or AICAR treatment. The present data show that AICAR stimulates AMPK phosphorylation and decreases ER stress response proteins in hypoxic placental villi. Further, the present data support the hypothesis that AICAR restores angiogenic balance by decreasing sFlt-1 rather than increasing VEGF secretion from placental villi. These findings suggest AICAR may improve placental function during pregnancies complicated by placental-ischemia.

scholarly journals Effect of hypoxic conditioning on functional fitness, balance and fear of falling in healthy older adults: a randomized controlled trial

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rafael Timon ◽  
Marta Camacho-Cardeñosa ◽  
Adrián González-Custodio ◽  
Guillermo Olcina ◽  
Narcis Gusi ◽  
...  
Keyword(s):  
Older Adults ◽  
Fear Of Falling ◽  
Controlled Trial ◽  
Training Group ◽  
Training Programme ◽  
Control Group ◽  
Functional Fitness ◽  
Healthy Older Adults ◽  
Hypoxia Exposure ◽  
Hypoxic Conditions

Abstract Background Hypoxic conditioning has been proposed as a new tool to mitigate the sarcopenia and enhance health-related function, but decrements in standing balance have been observed during hypoxia exposure. The aim of the study was to evaluate the effect of a hypoxic conditioning training on functional fitness, balance and fear of falling in healthy older adults. Methods A total of 54 healthy older adults (aged 65–75 years), who voluntarily participated in the study, were randomly divided into three groups: the control group (CON), the normoxia training group (NT) that performed strength training in normoxia, and the hypoxia training group (HT) that trained under moderate hypoxic conditions at a simulated altitude of 2500 m asl. The training programme that was performed during 24 weeks was similar in both experimental groups and consisted of a full-body workout with elastic bands and kettlebells (three sets × 12–15 reps). The Senior Fitness Test (SFT), the Single Leg Stance test (SLS) and the Short Falls Efficacy Scale-International (FES-I) were assessed before and after the intervention. Results Results showed that after training, either in normoxia or in hypoxia, the participants increased upper and lower body strength, and the aerobic endurance, and decreased the fear of falling. Conclusions The moderate hypoxic conditioning seems to be a useful tool to increase the functional capacity in healthy older adults without observing a decline in balance. Trial registration ClinicalTrials.gov NCT04281264. Registered February 9, 2019-Retrospectively registered.

scholarly journals Effect of hypoxia on purine metabolism of human skeletal muscle cells

Biotecnia ◽  
2021 ◽  
Vol 23 (2) ◽  
Author(s):  
Tania Zenteno-Savín ◽  
Crisalejandra Rivera-Pérez ◽  
Ramón Gaxiola-Robles ◽  
Norma Olguín-Monroy ◽  
Orlando Lugo-Lugo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Muscle Cells ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Purine Metabolism ◽  
Inosine Monophosphate Dehydrogenase ◽  
Inosine Monophosphate ◽  
Hypoxic Conditions ◽  
Human Skeletal Muscle Cells

Mammals experience some degree of hypoxia during their lifetime. In response to hypoxic challenge, mammalian cells orchestrate specific responses at transcriptional and posttranslational level which lead to changes in the purine metabolites in order to cope with threatening conditions. The aim of this study was to evaluate the response of the enzymes involved in the purine metabolism of human muscle cells to hypoxic conditions. Muscle cells in culture were exposed to hypoxia and the enzymatic activity of inosine monophosphate dehydrogenase (IMPDH), xanthine oxidase (XO), purine nucleoside phosphorylase (PNP) and hypoxanthine guanine phosphoribosyl transferase (HGPRT) as well as their transcript expression were quantified under normoxic and hypoxic conditions. Purine metabolite (hypoxanthine (HX), xanthine (X), uric acid (UA), inosine monophosphate (IMP), inosine, nicotinamide adenine dinucleotide (NAD+), adenosine, adenosine monophosphate (AMP), adenosine diphosphate (ADP), adenosine triphosphate (ATP), guanosine diphosphate (GDP) and guanosine triphosphate (GTP)) concentrations were also quantified. Significant reduction of IMPDH activity and HX and IMP concentrations (p < 0.05) were observed after hypoxia, suggesting a decrease of de novo synthesis of purines. After hypoxia a global reduction of transcripts was observed, suggesting a reduction of the metabolic machinery of purine metabolism to new steady states that balance ATP demand and ATP supply pathways.

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