A genetic program boosts mitochondrial function to power macrophage tissue invasion

SUMMARYMetabolic adaptation to changing demands underlies homeostasis. During inflammation or metastasis, cells leading migration into challenging environments require an energy boost, however what controls this capacity is unknown. We identify a previously unstudied nuclear protein, Atossa, as changing metabolism in Drosophila melanogaster immune cells to promote tissue invasion. Atossa’s vertebrate orthologs, FAM214A-B, can fully substitute for Atossa, indicating functional conservation from flies to mammals. Atossa increases mRNA levels of Porthos, an unstudied RNA helicase and two metabolic enzymes, LKR/SDH and GR/HPR. Porthos increases translation of a gene subset, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Respiration measurements and metabolomics indicate that Atossa and Porthos powers up mitochondrial oxidative phosphorylation to produce sufficient energy for leading macrophages to forge a path into tissues. As increasing oxidative phosphorylation enables many crucial physiological responses, this unique genetic program may modulate a wide range of cellular behaviors beyond migration.

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The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

International Journal of Molecular Sciences ◽

10.3390/ijms22136857 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6857

Author(s):

Samantha Bruno ◽

Manuela Mancini ◽

Sara De Santis ◽

Cecilia Monaldi ◽

Michele Cavo ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Cell Fate ◽

Myeloid Leukemia ◽

Hematologic Malignancy ◽

Bone Marrow Microenvironment ◽

Metabolic Adaptation ◽

Cell Fate Decisions ◽

Wide Range ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

Life ◽

10.3390/life11030242 ◽

2021 ◽

Vol 11 (3) ◽

pp. 242

Author(s):

Salvatore Nesci ◽

Fabiana Trombetti ◽

Alessandra Pagliarani ◽

Vittoria Ventrella ◽

Cristina Algieri ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Atp Synthase ◽

Mitochondrial Permeability Transition ◽

Ros Generation ◽

Protonmotive Force ◽

Mitochondrial Oxidative Phosphorylation ◽

F1fo Atp Synthase ◽

Functional Changes ◽

Age Related ◽

Mitochondrial Functions

Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases.

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Cellular effects of glycine and trehalose air-polishing powders on human gingival fibroblasts in vitro

Clinical Oral Investigations ◽

10.1007/s00784-021-04130-0 ◽

2021 ◽

Author(s):

Jens Weusmann ◽

James Deschner ◽

Jean-Claude Imber ◽

Anna Damanaki ◽

Natalia D. P. Leguizamón ◽

...

Keyword(s):

Wound Healing ◽

Cell Function ◽

Nuclear Translocation ◽

In Vitro Study ◽

Human Gingival Fibroblasts ◽

Mrna Levels ◽

Gingival Fibroblasts ◽

Air Polishing ◽

Wide Range

Abstract Objectives Air-polishing has been used in the treatment of periodontitis and gingivitis for years. The introduction of low-abrasive powders has enabled the use of air-polishing devices for subgingival therapy. Within the last decade, a wide range of different low-abrasive powders for subgingival use has been established. In this study, the effects of a glycine powder and a trehalose powder on human gingival fibroblasts (HGF) were investigated. Methods HGF were derived from three systemically and periodontally healthy donors. After 24 h and 48 h of incubation time, mRNA levels, and after 48 h, protein levels of TNFα, IL-8, CCL2, and VEGF were determined. In addition, NF-κB p65 nuclear translocation and in vitro wound healing were assessed. Statistical analysis was performed by ANOVA and post hoc Dunnett’s and Tukey’s tests (p < 0.05). Results Glycine powder significantly increased the expression of proinflammatory genes and showed exploitation of the NF-κB pathway, albeit trehalose powder hardly interfered with cell function and did not trigger the NF-κB pathway. In contrast to trehalose, glycine showed a significant inhibitory effect on the in vitro wound healing rate. Conclusion Subgingivally applicable powders for air-polishing devices can regulate cell viability and proliferation as well as cytokine expression. Our in vitro study suggests that the above powders may influence HGF via direct cell effects. Trehalose appears to be relatively inert compared to glycine powder.

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Impact of clock-associated Arabidopsis pseudo-response regulators in metabolic coordination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0900952106 ◽

2009 ◽

Vol 106 (17) ◽

pp. 7251-7256 ◽

Cited By ~ 152

Author(s):

Atsushi Fukushima ◽

Miyako Kusano ◽

Norihito Nakamichi ◽

Makoto Kobayashi ◽

Naomi Hayashi ◽

...

Keyword(s):

Circadian Clock ◽

Stress Responses ◽

Clock Genes ◽

Higher Plants ◽

Tricarboxylic Acid Cycle ◽

Integrated Analysis ◽

Response Regulators ◽

Triple Mutant ◽

Mitochondrial Functions ◽

Wide Range

In higher plants, the circadian clock controls a wide range of cellular processes such as photosynthesis and stress responses. Understanding metabolic changes in arrhythmic plants and determining output-related function of clock genes would help in elucidating circadian-clock mechanisms underlying plant growth and development. In this work, we investigated physiological relevance of PSEUDO-RESPONSE REGULATORS (PRR 9, 7, and 5) in Arabidopsis thaliana by transcriptomic and metabolomic analyses. Metabolite profiling using gas chromatography–time-of-flight mass spectrometry demonstrated well-differentiated metabolite phenotypes of seven mutants, including two arrhythmic plants with similar morphology, a PRR 9, 7, and 5 triple mutant and a CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1)-overexpressor line. Despite different light and time conditions, the triple mutant exhibited a dramatic increase in intermediates in the tricarboxylic acid cycle. This suggests that proteins PRR 9, 7, and 5 are involved in maintaining mitochondrial homeostasis. Integrated analysis of transcriptomics and metabolomics revealed that PRR 9, 7, and 5 negatively regulate the biosynthetic pathways of chlorophyll, carotenoid and abscisic acid, and α-tocopherol, highlighting them as additional outputs of pseudo-response regulators. These findings indicated that mitochondrial functions are coupled with the circadian system in plants.

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Hexokinase and glucokinases are essential for fitness and virulence in the pathogenic yeastCandida albicans

10.1101/448373 ◽

2018 ◽

Cited By ~ 1

Author(s):

Romain Laurian ◽

Karine Dementhon ◽

Bastien Doumèche ◽

Alexandre Soulard ◽

Thierry Noel ◽

...

Keyword(s):

Stress Responses ◽

Galleria Mellonella ◽

Glucose Repression ◽

Metabolic Adaptation ◽

Metabolic Flexibility ◽

Pathogenic Yeast ◽

Regulatory Pathways ◽

Metabolic Role ◽

Wide Range ◽

Hexose Phosphorylation

AbstractMetabolic flexibility promotes infection and commensal colonization by the opportunistic pathogenCandida albicans.Yeast cell survival depends upon assimilation of fermentable and non-fermentable locally available carbon sources. Physiologically relevant sugars like glucose and fructose are present at low level in host niches. However, because glucose is the preferred substrate for energy and biosynthesis of structural components, its efficient metabolization is fundamental for the metabolic adaptation of the pathogen. We explored and characterized theC. albicanshexose kinase system composed of one hexokinase (CaHxk2) and two glucokinases (CaGlk1 and CaGlk4). Using a set of mutant strains, we found that hexose phosphorylation is mostly assured by CaHxk2, which sustains growth on hexoses. Our data on hexokinase and glucokinase expression point out an absence of cross regulation mechanisms at the transcription level and different regulatory pathways. In the presence of glucose, CaHxk2 migrates in the nucleus and contributes to the glucose repression signaling pathway. In addition, CaHxk2 participates to oxidative, osmotic and cell wall stress responses, while glucokinases are overexpressed under hypoxia. Hexose phosphorylation is a key step necessary for filamentation, that is affected in the hexokinase mutant. Virulence of this mutant is clearly impacted in theGalleria mellonellaand macrophage models. Filamentation, glucose phosphorylation and stress response defects of the hexokinase mutant prevent host killing byC. albicans.By contributing to metabolic flexibility, stress answer response and morphogenesis, hexose kinase enzymes play an essential role in the virulence ofC. albicans.Author summaryThe pathogenic yeastC. albicansis both a powerful commensal and pathogen of humans that can infect wide range of organs and body sites. To grow in its host and establish an infection, the pathogen must assimilate carbon from these heterogenous environments.C. albicansregulates central carbon metabolism in a niche-specific manner, activating alternatively gluconeogenesis, glyoxylate cycle and the glycolytic metabolism. For yeast and other microorganisms, glucose is the preferred carbon and energy source and its accurate detection and metabolism is essential. However, the glycolytic hexose kinase system has not been investigated yet inC. albicans.In this report, we showed that hexokinase and glucokinases contribute to the fitness and virulence ofC. albicans.We revealed the main metabolic role of the hexokinase CaHxk2 which impacts on growth, glucose signalling, morphological transition and virulence. However, glucokinases contribute to the anoxic response and their implication in regulation processes is suggested.

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Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

Cancers ◽

10.3390/cancers10090337 ◽

2018 ◽

Vol 10 (9) ◽

pp. 337 ◽

Cited By ~ 17

Author(s):

Amruta Nayak ◽

Arvinder Kapur ◽

Lisa Barroilhet ◽

Manish Patankar

Keyword(s):

Ovarian Cancer ◽

Oxidative Phosphorylation ◽

Aerobic Glycolysis ◽

Ovarian Tumors ◽

Metabolic Adaptation ◽

Ovarian Cancer Stem Cells ◽

Critical Control Points ◽

Energy Needs ◽

Oxidative Phosphorylation Pathway ◽

Novel Therapeutic Strategies

Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation.

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Effects of dietary tributyrin on intestinal mucosa development, mitochondrial function and AMPK-mTOR pathway in weaned pigs

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-019-0394-x ◽

2019 ◽

Vol 10 (1) ◽

Author(s):

Chunchun Wang ◽

Shuting Cao ◽

Zhuojun Shen ◽

Qihua Hong ◽

Jie Feng ◽

...

Keyword(s):

Oxidative Stress ◽

Intestinal Mucosa ◽

Mitochondrial Function ◽

Control Group ◽

Mrna Levels ◽

Villus Height ◽

Weaned Pigs ◽

Glucose Transporter 2 ◽

Phosphorylation Level ◽

Mitochondrial Functions

Abstract Background The objective of this experiment was to investigate the influence of dietary tributyrin on intestinal mucosa development, oxidative stress, mitochondrial function and AMPK-mTOR signaling pathway. Methods Seventy-two pigs were divided into two treatments and received either a basal diet or the same diet supplemented with 750 mg/kg tributyrin. Each treatment has six replicates of six pigs. After 14 days, 6 pigs from each treatment were selected and the jejunal samples were collected. Results Results showed that supplemental tributyrin increased (P < 0.05) villus height and villus height: crypt depth of weaned pigs. Pigs fed tributyrin had greater (P < 0.05) RNA/DNA and protein/DNA ratios than pigs on the control group. The mRNA levels of sodium glucose transport protein-1 and glucose transporter-2 in the jejunum were upregulated (P < 0.05) in pigs fed the tributyrin diet. Dietary tributyrin supplementation lowered (P < 0.05) the malondialdehyde and hydrogen peroxide (H2O2) content in jejunum, enhanced (P < 0.05) the mitochondrial function, as demonstrated by decreased (P < 0.05) reactive oxygen species level and increased (P < 0.05) mitochondrial membrane potential. Furthermore, tributyrin increased (P < 0.05) mitochondrial DNA content and the mRNA abundance of genes related to mitochondrial functions, including peroxisomal proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, nuclear respiratory factor-1 in the jejunum. Supplementation with tributyrin elevated (P < 0.05) the phosphorylation level of AMPK and inhibited (P < 0.05) the phosphorylation level of mTOR in jejunum compared with the control group. Conclusions These findings suggest that dietary supplementation with tributyrin promotes intestinal mucosa growth, extenuates oxidative stress, improves mitochondrial function and modulates the AMPK-mTOR signal pathway of weaned pigs.

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Protein kinase C-α inhibits the repair of oxidative phosphorylation after S-(1,2-dichlorovinyl)-l-cysteine injury in renal cells

AJP Renal Physiology ◽

10.1152/ajprenal.00216.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. F64-F73 ◽

Cited By ~ 18

Author(s):

Xiuli Liu ◽

Malinda L. Godwin ◽

Grażyna Nowak

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Oxidative Phosphorylation ◽

Atpase Activity ◽

Mitochondrial Function ◽

Recovery Period ◽

Β Subunit ◽

Atp Production ◽

Kinase C ◽

Mitochondrial Functions

Previously, we showed that physiological functions of renal proximal tubular cells (RPTC) do not recover following S-(1,2-dichlorovinyl)-l-cysteine (DCVC)-induced injury. This study investigated the role of protein kinase C-α (PKC-α) in the lack of repair of mitochondrial function in DCVC-injured RPTC. After DCVC exposure, basal oxygen consumption (Qo2), uncoupled Qo2, oligomycin-sensitive Qo2, F1F0-ATPase activity, and ATP production decreased, respectively, to 59, 27, 27, 57, and 68% of controls. None of these functions recovered. Mitochondrial transmembrane potential decreased 53% after DCVC injury but recovered on day 4. PKC-α was activated 4.3- and 2.5-fold on days 2 and 4, respectively, of the recovery period. Inhibition of PKC-α activation (10 nM Go6976) did not block DCVC-induced decreases in mitochondrial functions but promoted the recovery of uncoupled Qo2, oligomycin-sensitive Qo2, F1F0-ATPase activity, and ATP production. Protein levels of the catalytic β-subunit of F1F0-ATPase were not changed by DCVC or during the recovery period. Amino acid sequence analysis revealed that α-, β-, and ε-subunits of F1F0-ATPase have PKC consensus motifs. Recombinant PKC-α phosphorylated the β-subunit and decreased F1F0-ATPase activity in vitro. Serine but not threonine phosphorylation of the β-subunit was increased during late recovery following DCVC injury, and inhibition of PKC-α activation decreased this phosphorylation. We conclude that during RPTC recovery following DCVC injury, 1) PKC-α activation decreases F0F1-ATPase activity, oxidative phosphorylation, and ATP production; 2) PKC-α phosphorylates the β-subunit of F1F0-ATPase on serine residue; and 3) PKC-α does not mediate depolarization of RPTC mitochondria. This is the first report showing that PKC-α phosphorylates the catalytic subunit of F1F0-ATPase and that PKC-α plays an important role in regulating repair of mitochondrial function.

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Sinapic Acid Inhibits Cardiac Hypertrophy via Activation of Mitochondrial Sirt3/SOD2 Signaling in Neonatal Rat Cardiomyocytes

Antioxidants ◽

10.3390/antiox9111163 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1163

Author(s):

Ui Jeong Yun ◽

Dong Kwon Yang

Keyword(s):

Cardiac Hypertrophy ◽

Antioxidant Properties ◽

Sinapic Acid ◽

Pharmacological Action ◽

Mitogen Activated Protein Kinase ◽

Neonatal Rat ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes ◽

Mitochondrial Functions ◽

Wide Range

Sinapic acid (SA) is a naturally occurring phenolic compound with antioxidant properties. It also has a wide range of pharmacological properties, such as anti-inflammatory, anticancer, and hepatoprotective properties. The present study aimed to evaluate the potential pharmacological effects of SA against hypertrophic responses in neonatal rat cardiomyocytes. In order to evaluate the preventive effect of SA on cardiac hypertrophy, phenylephrine (PE)-induced hypertrophic cardiomyocytes were treated with subcytotoxic concentrations of SA. SA effectively suppressed hypertrophic responses, such as cell size enlargement, sarcomeric rearrangement, and fetal gene re-expression. In addition, SA significantly inhibited the expression of mitogen-activated protein kinase (MAPK) proteins as pro-hypertrophic factors and protected the mitochondrial functions from hypertrophic stimuli. Notably, SA activated Sirt3, a mitochondrial deacetylase, and SOD2, a mitochondrial antioxidant, in hypertrophic cardiomyocytes. SA also inhibited oxidative stress in hypertrophic cardiomyocytes. However, the protective effect of SA was significantly reduced in Sirt3-silenced hypertrophic cardiomyocytes, indicating that SA exerts its beneficial effect through Sirt3/SOD signaling. In summary, this is the first study to reveal the potential pharmacological action and inhibitory mechanism of SA as an antioxidant against cardiac hypertrophy, suggesting that SA could be utilized for the treatment of cardiac hypertrophy.

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Stress signalling dynamics of the mitochondrial electron transport chain and oxidative phosphorylation system in higher plants

Annals of Botany ◽

10.1093/aob/mcz184 ◽

2019 ◽

Vol 125 (5) ◽

pp. 721-736 ◽

Cited By ~ 4

Author(s):

Corentin Dourmap ◽

Solène Roque ◽

Amélie Morin ◽

Damien Caubrière ◽

Margaux Kerdiles ◽

...

Keyword(s):

Climate Change ◽

Electron Transport ◽

Oxidative Phosphorylation ◽

Electron Transport Chain ◽

Plant Mitochondria ◽

Mitochondrial Electron Transport Chain ◽

Oxidative Phosphorylation System ◽

Transport Chain ◽

Wide Range ◽

Stress Signalling

Abstract Background Mitochondria play a diversity of physiological and metabolic roles under conditions of abiotic or biotic stress. They may be directly subjected to physico-chemical constraints, and they are also involved in integrative responses to environmental stresses through their central position in cell nutrition, respiration, energy balance and biosyntheses. In plant cells, mitochondria present various biochemical peculiarities, such as cyanide-insensitive alternative respiration, and, besides integration with ubiquitous eukaryotic compartments, their functioning must be coupled with plastid functioning. Moreover, given the sessile lifestyle of plants, their relative lack of protective barriers and present threats of climate change, the plant cell is an attractive model to understand the mechanisms of stress/organelle/cell integration in the context of environmental stress responses. Scope The involvement of mitochondria in this integration entails a complex network of signalling, which has not been fully elucidated, because of the great diversity of mitochondrial constituents (metabolites, reactive molecular species and structural and regulatory biomolecules) that are linked to stress signalling pathways. The present review analyses the complexity of stress signalling connexions that are related to the mitochondrial electron transport chain and oxidative phosphorylation system, and how they can be involved in stress perception and transduction, signal amplification or cell stress response modulation. Conclusions Plant mitochondria are endowed with a diversity of multi-directional hubs of stress signalling that lead to regulatory loops and regulatory rheostats, whose functioning can amplify and diversify some signals or, conversely, dampen and reduce other signals. Involvement in a wide range of abiotic and biotic responses also implies that mitochondrial stress signalling could result in synergistic or conflicting outcomes during acclimation to multiple and complex stresses, such as those arising from climate change.

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