bims-camemi Biomed news
on Mitochondrial metabolism in cancer
Issue of 2018‒09‒30
seven papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Cell Physiol Biochem. 2018 Sep 21. 49(5): 2022-2034
    Xia W, Yin J, Zhang S, Guo C, Li Y, Zhang Y, Zhang A, Jia Z, Chen H.
      BACKGROUND/AIMS: Although a number of reports documented the important role of parkin in mitophagy, emerging evidence also indicated additional functions of parkin besides mitophagy. The present study was undertaken to investigate the role of parkin in the regulation of ERRα/eNOS pathway in endothelial cells (ECs).METHODS: Mouse aortic endothelial cells (MAECs) and cardiac muscle HL-1 cells were transfected with parkin plasmid or siRNA. ERRα inhibitor XCT-790, autophagy inhibitor 3-MA and Bafilomycin A1, and caspase inhibitor Z-VAD-FMK were used to block autophagy or apoptosis. Western blotting was performed to examine the protein levels. Flow cytometry was applied to determine the cell apoptosis and ROS production. Mitochondrial membrane potential was measured using JC-1 and TMRM. Immunoprecipitation was performed to confirm the parkin effect on ERRα ubiquitination.
    RESULTS: Overexpression of parkin resulted in a significant reduction of total-eNOS and p-eNOS in parallel with the downregulation of ERRα (a regulator of eNOS) protein and the enhancement of ERRα ubiquitination. To test the role of ERRα in regulating eNOS in this experimental setting, we treated ECs with ERRα inhibitor and found a decrement of total-eNOS and p-eNOS. On the contrary, overexpression of ERRα increased the levels of total-eNOS and p-eNOS. Meanwhile, parkin overexpression induced mitochondrial dysfunction and cell apoptosis in both ECs and HL-1 cells. Finally, we confirmed that the parkin effect on the regulation of eNOS was independent of the autophagy and apoptosis.
    CONCLUSION: These findings suggested that parkin overexpression downregulated eNOS possibly through the ubiquitination of ERRα in endothelial cells.
    Keywords:  ERRα; Mitochondrial dysfunction; Parkin; Ubiquitination; eNOS
    DOI:  https://doi.org/10.1159/000493713
  2. J Biomed Inform. 2018 Sep 20. pii: S1532-0464(18)30184-9. [Epub ahead of print]
    Graudenzi A, Maspero D, Filippo MD, Gnugnolo M, Isella C, Mauri G, Medico E, Antoniotti M, Damani C.
      Effective stratification of cancer patients on the basis of their molecular make-up is a key open challenge. Given the altered and heterogenous nature of cancer metabolism, we here propose to use the overall expression of central carbon metabolism as biomarker to characterize groups of patients with important characteristics, such as response to ad-hoc therapeutic strategies and survival expectancy. To this end, we here introduce the data integration framework named Metabolic Reaction Enrichment Analysis (MaREA), which strives to characterize the metabolic deregulations that distinguish cancer phenotypes, by projecting RNA-seq data onto metabolic networks, without requiring metabolic measurements. MaREA computes a score for each network reaction, based on the expression of the set of genes encoding for the associated enzyme(s). The scores are first used as features for cluster analysis and then to rank and visualize in an organized fashion the metabolic deregulations that distinguish cancer sub-types. We applied our method to recent lung and breast cancer RNA-seq datasets from The Cancer Genome Atlas and we were able to identify subgroups of patients with significant differences in survival expectancy. We show how the prognostic power of MaREA improves when an extracted and further curated core model focusing on central carbon metabolism is used rather than the genome-wide reference network. The visualization of the metabolic differences between the groups with best and worst prognosis allowed to identify and analyze key metabolic properties related to cancer aggressiveness. Some of these properties are shared across different cancer (sub)types, e.g., the up-regulation of nucleic acid and amino acid synthesis, whereas some other appear to be tumor-specific, such as the up- or down-regulation of the phosphoenolpyruvate carboxykinase reaction, which display different patterns in distinct tumor (sub)types. These results might be soon employed to deliver highly automated diagnostic and prognostic strategies for cancer patients.
    Keywords:  Cancer metabolism; Genome-wide models; Metabolic networks; RNA-seq data; Sample stratification
    DOI:  https://doi.org/10.1016/j.jbi.2018.09.010
  3. Mol Biotechnol. 2018 Sep 22.
    Tang W, Luo C.
      RNA editing is a fundamental biochemical process relating to the modification of nucleotides in messenger RNAs of functional genes in cells. RNA editing leads to re-establishment of conserved amino acid residues for functional proteins in nuclei, chloroplasts, and mitochondria. Identification of RNA editing factors that contributes to target site recognition increases our understanding of RNA editing mechanisms. Significant progress has been made in recent years in RNA editing studies for both animal and plant cells. RNA editing in nuclei and mitochondria of animal cells and in chloroplast of plant cells has been extensively documented and reviewed. RNA editing has been also extensively documented on plant mitochondria. However, functional diversity of RNA editing factors in plant mitochondria is not overviewed. Here, we review the biological significance of RNA editing, recent progress on the molecular mechanisms of RNA editing process, and function diversity of editing factors in plant mitochondrial research. We will focus on: (1) pentatricopeptide repeat proteins in Arabidopsis and in crop plants; (2) the progress of RNA editing process in plant mitochondria; (3) RNA editing-related RNA splicing; (4) RNA editing associated flower development; (5) RNA editing modulated male sterile; (6) RNA editing-regulated cell signaling; and (7) RNA editing involving abiotic stress. Advances described in this review will be valuable in expanding our understanding in RNA editing. The diverse functions of RNA editing in plant mitochondria will shed light on the investigation of molecular mechanisms that underlies plant development and abiotic stress tolerance.
    Keywords:  Adenosine-to-inosine editing; Arabidopsis; Cytidine-to-uridine editing; Mitochondria; Pentatricopeptide repeat protein; RNA editing factor
    DOI:  https://doi.org/10.1007/s12033-018-0126-z
  4. Biochem Biophys Res Commun. 2018 Sep 19. pii: S0006-291X(18)31964-8. [Epub ahead of print]
    Xu W, Wang Y, Guo Y, Liu J, Ma L, Cao W, Yu B, Zhou Y.
      In diabetic cardiomyopathy, mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation, leading to metabolic disturbances. Fibroblast growth factor 19 (FGF19) acts as a metabolic regulator and may have a cardioprotective role on diabetic cardiomyopathy. In this study, we investigated the effects of FGF19 on energy metabolism. FGF19 treatment of diabetic hearts exhibited higher glucose uptake and lower lipid profiles, suggesting changes in energy metabolism. The protective effects of FGF19 prevented ventricular dysfunction in diabetic hearts and improved mitochondrial function by the upregulation of PGC-1α expression. On the other side, knockdown of PGC-1α by siRNA attenuated the effects of FGF19 on the enhancement of mitochondrial function and energy efficiency. Taken together, these results show that FGF19 exhibited improved mitochondrial efficiency, which might be associated with higher cardiac contractility in diabetic hearts. It is also of note that modulation of PGC-1α, which is responsible for the activation by FGF19, may be a therapeutic target for diabetic cardiomyopathy.
    Keywords:  Diabetic cardiomyopathy (DCM); Fibroblast growth factor 19 (FGF19); Mitochondrial energy homoeostasis; PGC-1α
    DOI:  https://doi.org/10.1016/j.bbrc.2018.09.046
  5. Mitochondrion. 2018 Sep 19. pii: S1567-7249(18)30011-4. [Epub ahead of print]
    Di Stadio A, Angelini C.
      
    Keywords:  Macrophages; Metabolites; Microglia; Mitochondria; Muscle atrophy
    DOI:  https://doi.org/10.1016/j.mito.2018.09.003
  6. J Ovarian Res. 2018 Sep 22. 11(1): 85
    Kalavska K, Minarik T, Vlkova B, Manasova D, Kubickova M, Jurik A, Mardiak J, Sufliarsky J, Celec P, Mego M.
      BACKGROUND: Patients with ovarian cancer represent a heterogeneous population with a variable prognosis and response to chemotherapy. Plasma DNA has been shown to have a prognostic value in different types of cancer including ovarian carcinoma. Whether total circulating DNA, which can be assessed much easier without knowing the tumor-specific mutations, has similar informative value is currently unknown. The aim of this study was to evaluate the prognostic value of extracellular DNA in advanced ovarian cancer.METHODS: This prospective study included 67 patients (pts) with ovarian cancer treated with 1st line paclitaxel and carboplatin (25 pts) and paclitaxel, carboplatin and bevacizumab (42 pts). Thirty-five patients had optimal surgical debulking before chemotherapy. Extracellular DNA was quantified using real time PCR before administration of chemotherapy (67 pts) and after 6 cycles of chemotherapy (44 pts).
    RESULTS: Total extracellular DNA (ecDNA), as well as extracellular DNA of nuclear (nDNA) and mitochondrial origin (mtDNA) significantly (p < 0.05) decreased after 6 cycles of chemotherapy (by 54%, 63% and 52%, respectively. Patients with stage I disease had significantly lower mtDNA compared to patients with stage II-IV (8604 vs. 16, 984 ge/mL, p = 0.03). Patients with lower baseline nDNA had superior progression-free (HR = 0.35 (0.14-0.86)) and overall survival (HR = 0.18 (0.04-0.77). The prognostic value of nDNA was confirmed independent of tumor stage and confirmed in multivariate analysis.
    CONCLUSIONS: Our data suggest that ecDNA of both, nuclear and mitochondrial origin could be added to prognostic markers in ovarian cancer. Analysis of ecDNA does not require the knowledge of tumor-specific mutations in contrast to the quantification of tumor-derived ecDNA. Study of the dynamics and cell type-specific source of the ecDNA could shed light on its biology in cancer and might help to direct the treatment of ovarian cancer.
    Keywords:  Extracellular DNA; Ovarian cancer; Plasma DNA; Prognostic marker
    DOI:  https://doi.org/10.1186/s13048-018-0459-z
  7. Mult Scler Relat Disord. 2018 Sep 06. pii: S2211-0348(18)30310-9. [Epub ahead of print]26 90-95
    Høglund RA, Polak J, Vartdal F, Holmøy T, Lossius A.
      BACKGROUND: B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate (DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whether the drug influences the cellular composition in the cerebrospinal fluid (CSF).METHODS: A cross-sectional study examining the cellular composition in blood and cerebrospinal fluid (CSF) from 10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment.
    RESULTS: Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MS patients (p = 0.0007), and the reduction correlated with treatment duration (rs = -0.75, p = 0.021). In the CSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to the other patients (p = 0.023), and there was a disproportionate decrease of plasmablasts (p = 0.031).
    CONCLUSION: The results of this exploratory study support a B-cell mediated mechanism of action for DMF in both blood and CSF.
    Keywords:  B cell; Cerebrospinal fluid; Dimethyl fumarate; Memory B cell; Multiple sclerosis; Plasmablast
    DOI:  https://doi.org/10.1016/j.msard.2018.08.032