THE RNA BINDING PROTEIN ZC3H10 COUPLES MITOCHONDRIAL FUNCTION AND IRON METABOLISM

Mitochondria play a crucial role in energy metabolism. Mitochondria have their own genome (mtDNA), whose replication and transcription are mainly regulated by the mitochondrial transcription factor A (Tfam). Recent researches demonstrate how mitochondria participate to a large number of cellular processes like cell cycle and differentiation. Our goal is to identify new mitochondrial regulators to light up the molecular mechanisms underlying mitochondrial function biology. We used a high throughput screening in 293 cells in order to identify positive mitochondrial regulators. By these means, we identified Zinc Finger CCCH-type containing 10 (Zc3h10) as the best hit. Following experiments demonstrated that Zc3h10 knockdown decreased mitochondrial function and differentiation in myotubes. RNA immunoprecipitation assay indicates that Zc3h10 is able to bind 410 transcripts. Several target genes are involved in energy metabolism and iron balance. Notably, Zc3h10 downregulation in C2C12 leads to iron overload while its overexpression restores ferric ion content to control levels. Collectively, our findings annotate Zc3h10 as a new mitochondrial regulator in skeletal muscle

On the nature of the X-ray absorption in the Seyfert 2 galaxy NGC 4507

We present results of the ASCA observation of the Seyfert 2 galaxy NGC 4507. The 0.5-10 keV spectrum is rather complex and consists of several components: (1) a hard X-ray power law heavily absorbed by a column density of about 3 10^23 cm^-2, (2) a narrow Fe Kalpha line at 6.4 keV, (3) soft continuum emission well above the extrapolation of the absorbed hard power law, (4) a narrow emission line at about 0.9 keV. The line energy, consistent with highly ionized Neon (NeIX), may indicate that the soft X-ray emission derives from a combination of resonant scattering and fluorescence in a photoionized gas. Some contribution to the soft X-ray spectrum from thermal emission, as a blend of Fe L lines, by a starburst component in the host galaxy cannot be ruled out with the present data.Comment: 8 pages, LateX, 5 figures (included). Uses mn.sty and epsfig.sty. To appear in MNRA

Mitochondrial dysfunction increases fatty acid β-oxidation and translates into impaired neuroblast maturation

The metabolic transition from anaerobic glycolysis and fatty acid \u3b2-oxidation to glycolysis coupled to oxidative phosphorylation is a key process for the transition of quiescent neural stem cells to proliferative neural progenitor cells. However, a full characterization of the metabolic shift and the involvement of mitochondria during the last step of neurogenesis, from neuroblasts to neuron maturation, is still elusive. Here, we describe a model of neuroblasts, Neuro2a cells, with impaired differentiation capacity due to mitochondrial dysfunction. Using a detailed biochemical characterization consisting of steady-state metabolomics and metabolic flux analysis, we find increased fatty acid \u3b2-oxidation as a peculiar feature of neuroblasts with altered mitochondria. The consequent metabolic switch favors neuroblast proliferation at the expense of neuron maturation

po 324 interferon regulatory factor 1 irf1 regulates inflammatory and metabolic phenotypes in pancreatic ductal adenocarcinoma

Introduction Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent neoplasia of the exocrine pancreas. This tumour is and is characterised by a pervasive heterogeneity, with the coexistence of a range of histological grades, from epithelial-like to mesenchymal-like features. We previously dissected the transcriptional and epigenetic networks underlying PDAC grading. We identified the association of low grade phenotypes with a cell-autonomous interferon-related signature. Therefore, we set out to investigate the sustainment of inflammatory and interferon-related signatures in well-differentiated pancreatic cancer cells, and to determine the role of this network in PDAC biology. Material and methods We used cell-line based models of cancer differentiation, xenografts and human samples. We used CRISPR-Cas9 mediated genome editing to delete the transcription factor IRF1 (Interferon Regulatory Factor 1) in low-grade PDAC cells. RNA-seq, metabolic assays (oxygraphy, steady state metabolomics, fluxomics) and cell biology assays were carried out in IRF1 wt and knock-out cell lines. Data validation in human PDAC samples was carried out by immunohistochemistry. Results and discussions We found that IRF1 is a transcription factor differentially expressed between low- and high-grade PDACs, both in cell lines and in human tumours. IRF1 deletion in low-grade cell lines reduced the expression of genes in the antigen processing and presentation pathways, while its overexpression promoted the expression of the same genes in high-grade cells, where they are normally not expressed. Furthermore, xenografted IRF1-deficient cell lines recruited fewer immune cells in vivo . IRF1 deletion also affected epithelial phenotypes, including growth rate, cell shape, motility and collagen remodelling ability. Alongside, we unveiled a role of IRF1 in the control of the metabolism of low-grade PDAC cells, consisting in the control of mitochondrial respiration and lipogenesis as well as of the overall lipid profile of these cells. Conclusion To conclude, our results provide hints on the regulatory networks controlling cell differentiation in human PDACs. We show that IRF1 acts as a pleiotropic regulator in the low grade component of PDACs, with wide effects on immunological and metabolic features of this cancer population. Our work reinforces the body of knowledge needed for the development of those therapeutic strategies aiming at exploiting immunological or metabolic pitfalls

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model

Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNAseq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management

Elovl5 is required for proper action potential conduction along peripheral myelinated fibers

Elovl5 elongates fatty acids with 18 carbon atoms and in cooperation with other enzymes guarantees the normal levels of very long‐chain fatty acids, which are necessary for a proper membrane structure. Action potential conduction along myelinated axons depends on structural integrity of myelin, which is maintained by a correct amount of fatty acids and a proper interaction between fatty acids and myelin proteins. We hypothesized that in Elovl5 (−/−) mice, the lack of elongation of Elovl5 substrates might cause alterations of myelin structure. The analysis of myelin ultrastructure showed an enlarged periodicity with reduced G‐ratio across all axonal diameters. We hypothesized that the structural alteration of myelin might affect the conduction of action potentials. The sciatic nerve conduction velocity was significantly reduced without change in the amplitude of the nerve compound potential, suggesting a myelin defect without a concomitant axonal degeneration. Since Elovl5 is important in attaining normal amounts of polyunsaturated fatty acids, which are the principal component of myelin, we performed a lipidomic analysis of peripheral nerves of Elovl5‐deficient mice. The results revealed an unbalance, with reduction of fatty acids longer than 18 carbon atoms relative to shorter ones. In addition, the ratio of saturated to unsaturated fatty acids was strongly increased. These findings point out the essential role of Elovl5 in the peripheral nervous system in supporting the normal structure of myelin, which is the key element for a proper conduction of electrical signals along myelinated nerves

Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements.

Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. In particular, catalogs of structural vari- ants (SVs) (variants R 50 bp) are incomplete, limiting the discovery of causative alleles for phenotypic vari- ation. Here, we resolve genome-wide SVs in 20 genetically distinct inbred mice with long-read sequencing. We report 413,758 site-specific SVs affecting 13% (356 Mbp) of the mouse reference assembly, including 510 previously unannotated coding variants. We substantially improve the Mus musculus transposable element (TE) callset, and we find that TEs comprise 39% of SVs and account for 75% of altered bases. We further utilize this callset to investigate how TE heterogeneity affects mouse embryonic stem cells and find multiple TE classes that influence chromatin accessibility. Our work provides a comprehensive analysis of SVs found in diverse mouse genomes and illustrates the role of TEs in epigenetic differences