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A genetic program boosts mitochondrial function to power macrophage tissue invasion (RNA-seq, sorted macrophages)

ABSTRACT: Metabolic 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 power up mitochondrial oxidative phosphorylation to produce sufficient energy for pioneer 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE167132 | GEO | 2021/12/15

REPOSITORIES: GEO

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Project description:Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle This model is described in the article: Creatine kinase in energy metabolic signaling in muscle Olav Kongas and Johannes H. G. M. van Beek Available from Nature Precedings Abstract: There has been much debate on the mechanism of regulation of mitochondrial ATP synthesis to balance ATP consumption during changing cardiac workloads. A key role of creatine kinase (CK) isoenzymes in this regulation of oxidative phosphorylation and in intracellular energy transport had been proposed, but has in the mean time been disputed for many years. It was hypothesized that high-energy phosphorylgroups are obligatorily transferred via CK; this is termed the phosphocreatine shuttle. The other important role ascribed to the CK system is its ability to buffer ADP concentration in cytosol near sites of ATP hydrolysis. Almost all of the experiments to determine the role of CK had been done in the steady state, but recently the dynamic response of oxidative phosphorylation to quick changes in cytosolic ATP hydrolysis has been assessed at various levels of inhibition of CK. Steady state models of CK function in energy transfer existed but were unable to explain the dynamic response with CK inhibited. The aim of this study was to explain the mode of functioning of the CK system in heart, and in particular the role of different CK isoenzymes in the dynamic response to workload steps. For this purpose we used a mathematical model of cardiac muscle cell energy metabolism containing the kinetics of the key processes of energy production, consumption and transfer pathways. The model underscores that CK plays indeed a dual role in the cardiac cells. The buffering role of CK system is due to the activity of myofibrillar CK (MMCK) while the energy transfer role depends on the activity of mitochondrial CK (MiCK). We propose that this may lead to the differences in regulation mechanisms and energy transfer modes in species with relatively low MiCK activity such as rabbit in comparison with species with high MiCK activity such as rat. The model needed modification to explain the new type of experimental data on the dynamic response of the mitochondria. We submit that building a Virtual Muscle Cell is not possible without continuous experimental tests to improve the model. In close interaction with experiments we are developing a model for muscle energy metabolism and transport mediated by the creatine kinase isoforms which now already can explain many different types of experiments. The model has been designed according to the spirit of the paper. The list of rate in the appendix has been corrected as follow: d[ATP]/dt = (-Vhyd -Vmmck +Jatp) / Vcyt d[ADP]/dt = ( Vhyd +Vmmck +Jadp) / Vcyt d[PCr]/dt = ( Vmmck +Jpcr ) / Vcyt d[Cr]/dt = (-Vmmck +Jpcr ) / Vcyt d[Pi]/dt = ( Vhyd + Jpi ) / Vcyt d[ATPi]/dt = (+Vsyn -Vmick -Jatp) / Vims d[ADPi]/dt = (-Vsyn +Vmick -Jadp) / Vims d[PCri]/dt = ( Vmick -Jpcr ) / Vims d[Cri]/dt = (-Vmick -Jpcr ) / Vims d[Pii]/dt = (-Vsyn -Jpi ) / Vims This model is hosted on BioModels Database and identified by: BIOMD0000000041 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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A genetic program boosts mitochondrial function to power macrophage tissue invasion (RNA-seq, sorted macrophages)

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