bims-camemi Biomed news
on Mitochondrial metabolism in cancer
Issue of 2018‒10‒28
ten papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. J Pharmacol Sci. 2018 Oct 04. pii: S1347-8613(18)30182-8. [Epub ahead of print]
    Liu L, Huang X, Gao J, Guo Y, Di Y, Sun S, Deng X, Cao J.
      Metabolic syndrome (MS) is a combination of symptoms characterized by central obesity, hypertension, hyperglycemia, and hyperlipidemia, which together increase the risk of heart disease, stroke and diabetes. In our study, we hypothesized that an EET-agonist (AUDA) would increase expression of PGC 1α and improve mitochondrial and endothelial functions, resulting in improved heart function in a rat model of MS. To investigate this, rats were randomly divided into four groups: 1) Control; 2) MS + ABCT; 3) MS + AUDA; and 4) MS + AUDA + SnMP. MS rats were fed a high-fructose diet for 16 weeks and developed elevated inflammatory mediators, oxidative stress, and significant decreases in fractional shortening and hemodynamic parameters, indicating cardiac dysfunction. Histology revealed myocardial fibrosis and myocyte hypertrophy. AUDA improves mitochondrial function proven by increase in mt copy number and ATP production and significantly increased expression of PGC-1α and HO-1 in the rats and normalization of inflammatory cytokines, oxidative stress, and improves in cardiac function and myocardial fibrosis. These benefits were reversed by SnMP. Furthermore, AUDA increases eNOS but decreases iNOS expression which improved endothelial function. We therefore demonstrate that endogenous EET upregulation plays a novel role in protecting the heart from MS by regulating mitochondrial and endothelial function.
    Keywords:  Epoxyeicoastrienoic acids; Heme oxygenase-1; Metabolic syndrome; Mitochondrial function; PGC-1α
    DOI:  https://doi.org/10.1016/j.jphs.2018.09.010
  2. Biochim Biophys Acta Mol Basis Dis. 2018 Oct 17. pii: S0925-4439(18)30388-0. [Epub ahead of print]
    Stanzani G, Duchen MR, Singer M.
      Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Myocardial dysfunction, often termed sepsis-induced cardiomyopathy, is a frequent complication and is associated with worse outcomes. Numerous mechanisms contribute to sepsis-induced cardiomyopathy and a growing body of evidence suggests that bioenergetic and metabolic derangements play a central role in its development; however, there are significant discrepancies in the literature, perhaps reflecting variability in the experimental models employed or in the host response to sepsis. The condition is characterised by lack of significant cell death, normal tissue oxygen levels and, in survivors, reversibility of organ dysfunction. The functional changes observed in cardiac tissue may represent an adaptive response to prolonged stress that limits cell death, improving the potential for recovery. In this review, we describe our current understanding of the pathophysiology underlying myocardial dysfunction in sepsis, with a focus on disrupted mitochondrial processes.
    Keywords:  Heart; Inflammation; Metabolism; Mitochondria; Organ failure; Sepsis
    DOI:  https://doi.org/10.1016/j.bbadis.2018.10.011
  3. Biochim Biophys Acta Mol Basis Dis. 2018 Oct 17. pii: S0925-4439(18)30389-2. [Epub ahead of print]
    Saari S, Garcia GS, Bremer K, Chioda MM, Andjelković A, Debes PV, Nikinmaa M, Szibor M, Dufour E, Rustin P, Oliveira MT, Jacobs HT.
      The alternative respiratory chain (aRC), comprising the alternative NADH dehydrogenases (NDX) and quinone oxidases (AOX), is found in microbes, fungi and plants, where it buffers stresses arising from restrictions on electron flow in the oxidative phosphorylation system. The aRC enzymes are also found in species belonging to most metazoan phyla, including some chordates and arthropods species, although not in vertebrates or in Drosophila. We postulated that the aRC enzymes might be deployed to alleviate pathological stresses arising from mitochondrial dysfunction in a wide variety of disease states. However, before such therapies can be contemplated, it is essential to understand the effects of aRC enzymes on cell metabolism and organismal physiology. Here we report and discuss new findings that shed light on the functions of the aRC enzymes in animals, and the unexpected benefits and detriments that they confer on model organisms. In Ciona intestinalis, the aRC is induced by hypoxia and by sulfide, but is unresponsive to other environmental stressors. When expressed in Drosophila, AOX results in impaired survival under restricted nutrition, in addition to the previously reported male reproductive anomalies. In contrast, it confers cold resistance to developing and adult flies, and counteracts cell signaling defects that underlie developmental dysmorphologies. The aRC enzymes may also influence lifespan and stress resistance more generally, by eliciting or interfering with hormetic mechanisms. In sum, their judicious use may lead to major benefits in medicine, but this will require a thorough characterization of their properties and physiological effects.
    Keywords:  AOX; Mitochondria; Mitochondrial disease; Reactive oxygen species; Thermogenesis
    DOI:  https://doi.org/10.1016/j.bbadis.2018.10.012
  4. Mol Cell Endocrinol. 2018 Oct 17. pii: S0303-7207(18)30288-0. [Epub ahead of print]
    González-Granillo M, Savva C, Li X, Fitch M, Pedrelli M, Hellerstein M, Parini P, Korach-André M, Gustafsson JÅ.
      OBJECTIVE: Estrogens play a key role in the distribution of adipose tissue and have their action by binding to both estrogen receptors (ER), α and β. Although ERβ has a role in the energy metabolism, limited data of the physiological mechanism and metabolic response involved in the pharmacological activation of ERβ is available.METHODS: For clinical relevance, non-ovariectomized female mice were subjected to high fat diet together with pharmacological (DIP - 4-(2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl)phenol) interventions to ERβ selective activation. The physiological mechanism was assessed in vivo by magnetic resonance imaging and spectroscopy, and oral glucose and intraperitoneal insulin tolerance test before and after DIP treatment. Liver and adipose tissue metabolic response was measured in HFD + vehicle and HFD + DIP by stable isotope, RNA sequencing and protein content.
    RESULTS: HFD-fed females treated with DIP had a tissue-specific response towards ERβ selective activation. The metabolic profile showed an improved fasting glucose level, insulin sensitivity and reduced liver steatosis.
    CONCLUSIONS: Our data demonstrate that selective activation of ERβ exerts a tissue-specific activity which promotes a beneficial effect on whole body metabolic response to obesity.
    Keywords:  Adipose tissue; Browning; Estrogen receptor β; Obesity
    DOI:  https://doi.org/10.1016/j.mce.2018.10.007
  5. J Immunol Methods. 2018 Oct 17. pii: S0022-1759(18)30192-3. [Epub ahead of print]
    Chakrabarti L, Mathew A, Li L, Han S, Klover J, Albanetti T, Hawley-Nelson P.
      Development of cell lines for biotherapeutic protein production requires screening large numbers of clones to identify and isolate high producing ones. As such, stable cell line generation is a time- and resource-intensive process. Therefore, there is an increasing need to enhance the selection efficiency of high-yielding clonal cell lines for cell line development projects by using high throughput screening of live cells for markers predictive of productivity. Single cell deposition by fluorescence activated cell sorting (FACS) is a commonly performed method for cloning to generate cell lines derived from a single recombinant cell. We have developed a novel strategy to identify higher productivity cells at the FACS step by leveraging a simple viable cell staining method that detects mitochondrial membrane potential (Ψm), a key indicator of cellular metabolic activity. We chose a dual-emission dye (Mito-ID, Enzo Life Sciences) that fluoresces green and orange in living cells with the intensity of the orange fluorescence being dependent on the cells Ψm status. Using available clonal cell lines with known productivity, or stable transfectant pools, we evaluated Ψm of cell populations with Mito-ID dye. We determined that the intensity of the Ψm fluorescent signal correlates with the known fed-batch titers of the producer clones, and that cell sorting based on an optimal Ψm staining intensity selectively enriches for higher producing clones from nonclonal transfectant pools. These clones are phenotypically stable for recombinant protein production. Furthermore, the strategy has been successfully applied to identifying higher producing cell lines for a range of antibody molecular formats. Using this method, we can combine an enriching step for high producers with the cloning step, thereby saving time and resources in cell line development.
    Keywords:  Cell line development; Cell sorting; Enrichment; Mitochondrial membrane potential; Productivity
    DOI:  https://doi.org/10.1016/j.jim.2018.10.007
  6. Adv Clin Chem. 2018 ;pii: S0065-2423(18)30036-2. [Epub ahead of print]87 1-36
    Zeng Y, Ren K, Zhu X, Zheng Z, Yi G.
      Long noncoding RNAs (lncRNAs) are an important group of pervasive noncoding RNAs (>200nt) proposed to be crucial regulators of numerous physiological and pathological processes. Through interactions with RNA, chromatin, and protein, lncRNAs modulate mRNA stability, chromatin structure, and the function of proteins (including transcription factors). In addition, to their well-known roles in the modulation of cell growth, apoptosis, neurological disease progression and cancer metastasis, these large molecules have also been identified as likely mediators of lipid metabolism. In particular, lncRNAs orchestrate adipogenesis; fatty acid, cholesterol, and phospholipid metabolism and transport; and the formation of high-density and low-density lipoproteins (HDLs and LDLs). LncRNAs also appear to target several transcription factors that play essential roles in the regulation of lipid metabolism, such as liver X receptors (LXRs), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptor γ (PPARγ). Better understanding the regulatory roles of lncRNAs in dyslipidemia, atherosclerosis, and adipogenesis will reveal appropriate strategies to treat these diseases. In this review, we review recent progress in lncRNA-mediated regulation of lipid metabolism, as well as its role in the regulation of adipogenesis.
    Keywords:  Adipogenesis; Dyslipidemias; Lipids metabolism; Long non-coding RNAs; Metabolic disease
    DOI:  https://doi.org/10.1016/bs.acc.2018.07.001
  7. Cell Calcium. 2018 Oct 12. pii: S0143-4160(18)30181-7. [Epub ahead of print]
    Parys JB.
      STAT3 is a pleiotropic prosurvival transcription factor with functions in nucleus and mitochondria. Avalle et al. (Cell Death Diff., 2018) now present evidence that STAT3 also promotes IP3R3 degradation at the endoplasmic reticulum, thereby limiting Ca2+ transfer to the mitochondria and thus supporting cellular survival via an alternate pathway.
    Keywords:  Apoptosis; ER-mitochondria contact sites; IP(3) receptor; Oncogenes; STAT3
    DOI:  https://doi.org/10.1016/j.ceca.2018.10.002
  8. Biochimie. 2018 Oct 18. pii: S0300-9084(18)30291-8. [Epub ahead of print]156 118-122
    Armas AM, Balparda M, Terenzi A, Busi MV, Pagani MA, Gomez-Casati DF.
      Frataxin plays a key role in cellular iron homeostasis of different organisms. It is engaged in several activities at the FeS cluster assembly machinery and it is also involved in heme biosynthesis. In plants, two genes encoding ferrochelatases (FC1 and FC2) catalyze the incorporation of iron into protoporphyrin IX in the last stage of heme synthesis in chloroplasts. Despite ferrochelatases are absent from other cell compartments, a remaining ferrochelatase activity has been observed in plant mitochondria. Here we analyze the possibility that frataxin acts as the iron donor to protoporphyrin IX for the synthesis of heme groups in plant mitochondria. Our findings show that frataxin catalyzes the formation of heme in vitro when it is incubated with iron and protoporphyrin IX. When frataxin is combined with AtNFS1 and AtISD11 the ferrochelatse activity is increased. These results suggest that frataxin could be the iron donor in the final step of heme synthesis in plant mitochondria, and constitutes an important advance in the elucidation of the mechanisms of heme synthesis in plants.
    Keywords:  Ferrochelatase; Heme; Mitochondria; frataxin
    DOI:  https://doi.org/10.1016/j.biochi.2018.10.009
  9. J Physiol Pharmacol. 2018 Jun;69(3):
    De Assis GG, Gasanov EV, de Sousa MBC, Kozacz A, Murawska-Cialowicz E.
      Currently, literature has accumulated great knowledge over the effect of exercise on the neurotrophin named brain derived neurotrophic factor (BDNF) and its role in neuronal plasticity. However, there is no enough discussion about how the exercise is related to enrichment of BDNF in specific metabolic properties. This review provides the current evidences regarding aerobic metabolism relation to BDNF concentrations in healthy individuals. A PICOS strategy was applied considering the mesh terms for: P - healthy subjects; I - physical exercise; C - aerobic metabolism demands; O - BDNF concentrations; S - before and after aerobic exercise; on PubMed, Scopus and Medline databases. Studies presenting at least one session the exercise with reports of BDNF analysis before and after were included. Reviews, letters, case-reports, articles not written in English, non- published or involving non-healthy populations were excluded. Compiling results, it was possible to observe a close interaction between different aerobic energy demands from the exercise models and the responses of BDNF, suggesting thus that increases in BDNF concentrations are associated to the amount of aerobic energy required by exercise in a dose-dependent manner. Moreover, the dynamics of BDNF synthesis and reuptake resemble the functioning of the metabolic systems of aerobic energy generation, with which they share a co-transcriptional factor dependence.
    DOI:  https://doi.org/10.26402/jpp.2018.3.12
  10. Mol Cancer. 2018 Oct 20. 17(1): 152
    Lim MMK, Wee JWK, Soong JC, Chua D, Tan WR, Lizwan M, Li Y, Teo Z, Goh WWB, Zhu P, Tan NS.
      Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-κB signaling pathways. ANGPTL4 deficiency reduced IC50 of anti-tumor drugs and enhanced apoptosis of cancer cells. In vivo suppression of ANGPTL4 led to higher accumulation of cisplatin-DNA adducts in primary and metastasized tumors, and a reduced metastatic tumor load. ANGPTL4 empowered cancer cells metabolic flexibility during EMT, securing ample cellular energy that fuels multiple ABC transporters to confer EMT-mediated chemoresistance. It suggests that metabolic strategies aimed at suppressing ABC transporters along with energy deprivation of EMT cancer cells may overcome drug resistance.
    Keywords:  ATP-binding cassette transporters; Angiopoietin-like 4; Epithelial-mesenchymal transition; Multi-drug resistance
    DOI:  https://doi.org/10.1186/s12943-018-0904-z