Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

International audienceBiogenesis of iron-sulfur clusters (ISC) is essential to almost all forms of life and involves complex protein machineries. This process is initiated within the mitochondrial matrix by the ISC assembly machinery. Cohort and case report studies have linked mutations in ISC assembly machinery to severe mitochondrial diseases. The voltage-dependent anion channel (VDAC) located within the mitochondrial outer membrane regulates both cell metabolism and apoptosis. Recently, the C-terminal truncation of the VDAC1 isoform, termed VDAC1-ΔC, has been observed in chemoresistant late-stage tumor cells grown under hypoxic conditions with activation of the hypoxia-response nuclear factor HIF-1α. These cells harbored atypical enlarged mitochondria. Here, we show for the first time that depletion of several proteins of the mitochondrial ISC machinery in normoxia leads to a similar enlarged mitochon-dria phenotype associated with accumulation of VDAC1-ΔC. This truncated form of VDAC1 accumulates in the absence of HIF-1α and HIF-2α activations and confers cell resistance to drug-induced apoptosis. Furthermore, we show that when hypoxia and siRNA knock-down of the ISC machinery core components are coupled, the cell phenotype is further accentuated , with greater accumulation of VDAC1-ΔC. Interestingly, we show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis. Finally, we have identified the mitochondria-associated membrane (MAM) localized Fe-S protein CISD2 as a link between ISC machinery downregulation and accumulation of anti-apoptotic VDAC1-ΔC. Our results are the first to associate dysfunction in Fe-S cluster biogenesis with cleavage of VDAC1, a form which has previously been shown to promote tumor resistance to chemotherapy, and raise new perspectives for targets in cancer therapy

Wake vortex detection, prediction and decision support tools in SESAR program

airports, surface operation on the runway is the limiting factor for the overall throughput; specifically the fixed and overly conservative ICAO wake turbulence separation minima. The wake turbulence hazardous flows can dissipate quicker because of decay due to air turbulence or be transported out of the way on oncoming traffic by cross-wind, yet wake turbulence separation minima do not take into account wind conditions. Indeed, for safety reasons, most airports assume a worst-case scenario and use conservative separations; the interval between aircraft taking off or landing therefore often amounts to several minutes. However, with the aid of accurate wind data and precise measurements of wake vortex by radar sensors, more efficient intervals can be set, particularly when weather conditions are stable. Depending on traffic volume, these adjustments can generate capacity gains, which have major commercial benefits. This paper presents the developments of a wake turbulence system supporting increased throughput as part of the European ATM research program SESAR. This wake turbulence system is designed to, punctually or permanently, reduce landing and departure wake turbulence separations, thus increasing the runway throughput in such a way that arrival demand peaks and departure delays are safety absorbed. This global objective is by deploying radar sensors to deliver real-time position and strength information of the wake vortices and to assess wind conditions including ambient air turbulence via Eddy Dissipation Rate (EDR). To further address the optimization of throughput, two extensions for the use of wake turbulence system are considered for the terminal area and the runway rollout. These extensions connect the ground system with the aircraft to maximize benefits. The first application is the optimization of aircraft sequence via point-merge procedure, which is part of interval management operational improvement. The second application relates to the optimization of runway exit based on assessment of runway condition and aircraft-based braking capability to select the best runway exit for both the aircraft objectives and the runway throughput

Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection

Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% b-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type b-catenin) and perivenous-type (mutant b-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was downregulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection

Promoter DNA Hypermethylation and Gene Repression in Undifferentiated Arabidopsis Cells

María Berdasco is with the Spanish National Cancer Centre, University of Oviedo, and Catalan Institute of Oncology; Rubén Alcázar is with University of Barcelona; María Victoria García-Ortiz is with University of Córdoba; Esteban Ballestar is with the Spanish National Cancer Centre; Agustín F. Fernández is with the Spanish National Cancer Centre; Teresa Roldán-Arjona is with University of Córdoba; Antonio F. Tiburcio is with University of Barcelona; Teresa Altabella is with University of Barcelona; Nicolas Buisine is with CNRS; Hadi Quesneville is with INRA; Antoine Baudry is with INRA; Loïc Lepiniec is with INRA; Miguel Alaminos is with University of Granada; Roberto Rodríguez is with University of Oviedo; Alan Lloyd is with UT Austin; Vincent Colot is with CNRS; Judith Bender is with Johns Hopkins University; María Jesús Canal is with University of Oviedo; Manel Esteller is with the Spanish National Cancer Centre and Catalan Institute of Oncology; Mario F. Fraga is with the Spanish National Cancer Centre and Spanish National Centre for Biotechnology.Maintaining and acquiring the pluripotent cell state in plants is critical to tissue regeneration and vegetative multiplication. Histone-based epigenetic mechanisms are important for regulating this undifferentiated state. Here we report the use of genetic and pharmacological experimental approaches to show that Arabidopsis cell suspensions and calluses specifically repress some genes as a result of promoter DNA hypermethylation. We found that promoters of the MAPK12, GSTU10 and BXL1 genes become hypermethylated in callus cells and that hypermethylation also affects the TTG1, GSTF5, SUVH8, fimbrin and CCD7 genes in cell suspensions. Promoter hypermethylation in undifferentiated cells was associated with histone hypoacetylation and primarily occurred at CpG sites. Accordingly, we found that the process specifically depends on MET1 and DRM2 methyltransferases, as demonstrated with DNA methyltransferase mutants. Our results suggest that promoter DNA methylation may be another important epigenetic mechanism for the establishment and/or maintenance of the undifferentiated state in plant cells.This work was supported by the Health (FIS01-04) (PI061267), Education and Science (I+D+I MCYT08-03, FU2004-02073/BMC and Consolider MEC09-05) Departments of the Spanish Government, the European Grant TRANSFOG LSHC-CT-2004-503438, and the Spanish Association Against Cancer (AECC). M.B. is funded by the Association Against Cancer (AECC).Cellular and Molecular Biolog