bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒05‒19
forty-two papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Semin Cell Dev Biol. 2019 May 11. pii: S1084-9521(18)30202-7. [Epub ahead of print]
    Schmidt C, Sciacovelli M, Frezza C.
      Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation, but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the step wise neoplastic progression after FH loss.
    Keywords:  FH; cancer; fumarate; metabolism; mitochondria
  2. Nat Commun. 2019 May 15. 10(1): 2172
    Kanemoto N, Okamoto T, Tanabe K, Shimada T, Minoshima H, Hidoh Y, Aoyama M, Ban T, Kobayashi Y, Ando H, Inoue Y, Itotani M, Sato S.
      Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.
  3. Mitochondrion. 2019 May 14. pii: S1567-7249(18)30177-6. [Epub ahead of print]
    Dawei L, Zhenyu W, Valérie N, Marta L, Delphine M, Grégoire V, Rodolphe F, Catherine B.
      Cyclic adenosine monophosphate (cAMP) production regulates certain aspects of mitochondria function in rodent cardiomyocytes, such as ATP production, oxygen consumption, calcium import and mitochondrial permeability transition (MPT), but how this cAMP pool is controlled is not well known. Here, expression, localization and activity of several cAMP-degrading enzymes, i.e. phosphodiesterases (PDEs), were investigated in isolated rodent cardiac mitochondria. In contrast to the heart ventricle where PDE4 is the major PDE, in cardiac mitochondria, cGMP-stimulated PDE2 activity was largest than PDE3 and PDE4 activities. PDE2 expression was mainly detected in subsarcolemmal mitochondria in association with the inner membrane rather than in interfibrillar mitochondria. PDE2, 3 and 4 activities were further confirmed in neonatal rat cardiomyocytes by real time FRET analysis. In addition, the pharmacological inhibition or the cardiac-specific overexpression of PDE2 modulated mitochondrial membrane potential loss, MPT and calcium import. In mitochondria isolated from PDE2 transgenic mice with a cardiac selective PDE2 overexpression, the oxidative phosphorylation (OXPHOS) was significantly lower than in wild-type mice, but stimulated by cGMP. Thus, cAMP degradation by PDEs represents a new regulatory mechanism of mitochondrial function.
    Keywords:  Calcium; Mitochondrial membrane potential; PDE; Respiration; cAMP
  4. Biochem J. 2019 May 15. pii: BCJ20190182. [Epub ahead of print]
    Goldberg EJ, Buddo KA, McLaughlin KL, Fernandez RF, Pereyra AS, Psaltis CE, Lin CT, Hagen JT, Boykov IN, Nguyen TK, Gowdy KM, Ellis JM, Neufer PD, McClung JM, Fisher-Wellman KH.
      Alterations to branched chain-keto acid (BCKA) oxidation have been implicated in a wide variety of human diseases, ranging from diabetes to cancer. Although global shifts in BCKA metabolism-evident by gene transcription, metabolite profiling, and in vivo flux analyses have been documented across various pathological conditions, the underlying biochemical mechanism(s) within the mitochondrion remain largely unknown. In vitro experiments using isolated mitochondria represent a powerful biochemical tool for elucidating the role of the mitochondrion in driving disease. Such analyses have routinely been utilized across disciplines to shed valuable insight on mitochondrial-linked pathologies. That said, few studies have attempted to model in vitro BCKA oxidation in isolated organelles. The impetus for the present study stemmed from the knowledge that complete oxidation of each of the three BCKAs involves a reaction dependent upon bicarbonate and ATP, both of which are not typically included in respiration experiments.  Based on this, it was hypothesized that the inclusion of exogenous bicarbonate and stimulation of respiration using physiological shifts in ATP free energy, rather than excess ADP, would allow for maximal BCKA-supported respiratory flux in isolated mitochondria. This hypothesis was confirmed in mitochondria from several mouse tissues, including heart, liver and skeletal muscle. What follows is a thorough characterization and validation of a novel biochemical tool for investigating BCKA metabolism in isolated mitochondria.
    Keywords:  amino acid metabolism; bioenergetics; c; electron transport chain; mitochondria
  5. J Biol Chem. 2019 May 16. pii: jbc.AC119.008656. [Epub ahead of print]
    Agarwal E, Altman BJ, Seo JH, Ghosh JC, Kossenkov AV, Tang HY, Krishn SR, Languino LR, Gabrilovich DI, Speicher DW, Dang CV, Altieri DC.
      The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, and bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species (ROS) production and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo. We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrial OXPHOS pathways could offer an actionable therapeutic target in the clinic.
    Keywords:  Myc (c-Myc); TRAP1; invasion; metabolism; metastasis; mitochondria; oxidative phosphorylation
  6. Clin Chem. 2019 May 17. pii: clinchem.2018.299651. [Epub ahead of print]
    Subramaniam S, Jeet V, Clements JA, Gunter JH, Batra J.
      BACKGROUND: Metabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENT: miRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.
    SUMMARY: In this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.
  7. Med Hypotheses. 2019 Jun;pii: S0306-9877(19)30160-4. [Epub ahead of print]127 120-128
    Tan DX.
      Here, a new theory of aging is proposed. This new theory is referred as the Host-Mitochondria Intracellular Innate Immune Theory of Aging (HMIIITA). The main point of this theory is that the aging is rooted from an evolutionary competition, that is, a never ending coevolutionary race between host cells and mitochondria. Mitochondria are the descendants of bacteria. The host cells will inevitably sense their bacterial origin, particularly their circular mtDNA. The host intracellular innate immune pressure (HIIIP) aims to eliminate mtDNA as more as possible while mitochondria have to adapt the HIIIP for survival. Co-evolution is required for both of them. From biological point of view, the larger, the mtDNA, the higher, the chance, it becomes the target of HIIIP. As a result, mitochondria have to reduce their mtDNA size via deletion. This process has last for 1.5-2 billion yeas and the result is that mitochondria have lost excessive 95% of their DNA. This mtDNA deletion is not associated with free radical attack but a unique trait acquired during evolution. In the postmitotic cells, the deletion is passively selected by the mitochondrial fission-fusion cycles. Eventually, the accumulation of deletion will significantly jeopardize the mitochondrial function. The dysfunctional mitochondria no longer provide sufficient ATP to support host cells' continuous demanding for growth. At this stage, the cell or the organism aging is inevitable.
    Keywords:  Aging; Evolution; Host immunity; Intracellular innate immunity; Mitochondria
  8. Trends Biochem Sci. 2019 May 14. pii: S0968-0004(19)30082-9. [Epub ahead of print]
    Austin S, Nowikovsky K.
      Mitochondrial function is essential for life. Therefore, it is unsurprising that perturbations in mitochondrial function have wide-ranging consequences in the cell. High-throughput screening has identified essential genes required for cellular survival and fitness. One such gene is LETM1. The undisputed function of LETM1 from yeast to human is to maintain the mitochondrial osmotic balance. Osmotic imbalance has been demonstrated to affect mitochondrial morphology, dynamics, and, more recently, metabolism. Whether conservation of osmotic homeostasis by LETM1 occurs by extrusion of excess mitochondrial potassium (K+), calcium (Ca2+), or both has been a matter of dispute over the past 10 years. In this Opinion, we report and discuss recent findings on LETM1 structure, essentiality, and function and its involvement in Wolf-Hirschhorn syndrome (WHS) and seizures.
    Keywords:  LETM1; Wolf–Hirschhorn syndrome; calcium; metabolism; mitochondria; potassium
  9. Biology (Basel). 2019 May 11. pii: E33. [Epub ahead of print]8(2):
    Montgomery MK.
      Obesity, insulin resistance and type 2 diabetes are accompanied by a variety of systemic and tissue-specific metabolic defects, including inflammation, oxidative and endoplasmic reticulum stress, lipotoxicity, and mitochondrial dysfunction. Over the past 30 years, association studies and genetic manipulations, as well as lifestyle and pharmacological invention studies, have reported contrasting findings on the presence or physiological importance of mitochondrial dysfunction in the context of obesity and insulin resistance. It is still unclear if targeting mitochondrial function is a feasible therapeutic approach for the treatment of insulin resistance and glucose homeostasis. Interestingly, recent studies suggest that intact mitochondria, mitochondrial DNA, or other mitochondrial factors (proteins, lipids, miRNA) are found in the circulation, and that metabolic tissues secrete exosomes containing mitochondrial cargo. While this phenomenon has been investigated primarily in the context of cancer and a variety of inflammatory states, little is known about the importance of exosomal mitochondrial transfer in obesity and diabetes. We will discuss recent evidence suggesting that (1) tissues with mitochondrial dysfunction shed their mitochondria within exosomes, and that these exosomes impair the recipient's cell metabolic status, and that on the other hand, (2) physiologically healthy tissues can shed mitochondria to improve the metabolic status of recipient cells. In this context the determination of whether mitochondrial transfer in obesity and diabetes is a friend or foe requires further studies.
    Keywords:  exosomes; insulin resistance; mitochondrial dysfunction; mitochondrial transfer; type 2 diabetes
  10. Nature. 2019 May 15.
    Lieber T, Jeedigunta SP, Palozzi JM, Lehmann R, Hurd TR.
      Mitochondria contain their own genomes that, unlike nuclear genomes, are inherited only in the maternal line. Owing to a high mutation rate and low levels of recombination of mitrochondrial DNA (mtDNA), special selection mechanisms exist in the female germline to prevent the accumulation of deleterious mutations1-5. However, the molecular mechanisms that underpin selection are poorly understood6. Here we visualize germline selection in Drosophila using an allele-specific fluorescent in situ-hybridization approach to distinguish wild-type from mutant mtDNA. Selection first manifests in the early stages of Drosophila oogenesis, triggered by reduction of the pro-fusion protein Mitofusin. This leads to the physical separation of mitochondrial genomes into different mitochondrial fragments, which prevents the mixing of genomes and their products and thereby reduces complementation. Once fragmented, mitochondria that contain mutant genomes are less able to produce ATP, which marks them for selection through a process that requires the mitophagy proteins Atg1 and BNIP3. A reduction in Atg1 or BNIP3 decreases the amount of wild-type mtDNA, which suggests a link between mitochondrial turnover and mtDNA replication. Fragmentation is not only necessary for selection in germline tissues, but is also sufficient to induce selection in somatic tissues in which selection is normally absent. We postulate that there is a generalizable mechanism for selection against deleterious mtDNA mutations, which may enable the development of strategies for the treatment of mtDNA disorders.
  11. J Biol Chem. 2019 May 16. pii: jbc.RA118.006074. [Epub ahead of print]
    Ghosh S, Wicks SE, Vandanmagsar B, Mendoza TM, Bayless DS, Salbaum JM, Dearth SP, Campagna SR, Mynatt RL, Noland RC.
      Mitochondrial lipid overload in skeletal muscle contributes to insulin resistance and strategies limiting this lipid pressure improve glucose homeostasis; however, comprehensive cellular adaptations that occur in response to such an intervention have not been reported. Herein mice with skeletal muscle-specific deletion of carnitine palmitoyltransferase 1b (Cpt1bM-/-), which limits mitochondrial lipid entry, were fed a moderate fat (25%) diet and samples were subjected to a multi-modal analysis merging transcriptomics, proteomics, and non-targeted metabolomics to characterize the coordinated multi-level cellular responses that occur when mitochondrial lipid burden is mitigated. Limiting mitochondrial fat entry predictably improves glucose homeostasis; however, remodeling of glucose metabolism pathways pale in comparison to adaptations in amino acid and lipid metabolism pathways, shifts in nucleotide metabolites, and biogenesis of mitochondria and peroxisomes. Despite impaired fat utilization, Cpt1bM-/- mice have increased acetyl-CoA (14-fold) and NADH (2-fold), indicating metabolic shifts yield sufficient precursors to meet energy demand; however, this doesn't translate to enhance energy status as Cpt1bM-/- mice have low ATP and high AMP levels, signifying energy deficit. Comparative analysis of transcriptomic data with disease-associated gene-sets not only predicted reduced risk of glucose metabolism disorders, but were also consistent with lower risk for hepatic steatosis, cardiac hypertrophy, and premature death. Collectively these results suggest induction of metabolic inefficiency under conditions of energy surfeit likely contribute to improvements in metabolic health when mitochondrial lipid burden is mitigated. Moreover, the breadth of disease states to which mechanisms induced by muscle-specific Cpt1b inhibition may mediate health benefits could be more extensive than previously predicted.
    Keywords:  fatty acid metabolism; genomics; glucose metabolism; lipid oxidation; metabolomics; mitochondria; peroxisome; proteomics; skeletal muscle metabolism; systems biology
  12. Curr Protoc Pharmacol. 2019 May 13. e59
    Bhosale G, Duchen MR.
      Mitochondria act as 'sinks' for Ca2+ signaling, with mitochondrial Ca2+ uptake linking physiological stimuli to increased ATP production. However, mitochondrial Ca2+ overload can induce a cellular catastrophe by opening of the mitochondrial permeability transition pore (mPTP). This pore is a large conductance pathway in the inner mitochondrial membrane that causes bioenergetic collapse and appears to represent a final common path to cell death in many diseases. The role of the mPTP as a determinant of disease outcome is best established in ischemia/reperfusion injury in the heart, brain, and kidney, and it is also implicated in neurodegenerative disorders and muscular dystrophies. As the probability of pore opening can be modulated by drugs, it represents a useful pharmacological target for translational research in drug discovery. Described in this unit is a protocol utilizing isolated mitochondria to quantify this phenomenon and to develop a high-throughput platform for phenotypic screens for Ca2+ dyshomeostasis. © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
    Keywords:  calcium; mitochondria; permeability transition pore
  13. Diagn Pathol. 2019 May 15. 14(1): 42
    Ugarte-Camara M, Fernandez-Prado R, Lorda I, Rossello G, Gonzalez-Enguita C, Cannata-Ortiz P, Ortiz A.
      BACKGROUND: According to WHO, succinate dehydrogenase (SDH)-deficient renal cell carcinoma is characterized by negative immunostaining for SDHB, which remains positive in non-tumor tissue despite germline mutations in the SDHB gene. We now report a patient with a SDHB mutation, c.166_170del (p.Pro56Tyrfs*5) who developed renal cell carcinomas with characteristic morphological features of SDH-deficient renal cell carcinoma but had positive SDHB immunostaining.CASE PRESENTATION: Within a 6-year period, the patient developed two different renal cell carcinomas, which had characteristic morphological features of SDH-deficient renal cell carcinoma (uniform cells characteristically displaying eosinophilic granular material intermixed with fewer cells exhibiting clear intracytoplasmic inclusions and bland centered nuclei) but displayed immunohistochemistry for SDHB with a cytoplasmic granular positivity (mitochondrial pattern) in tumor cells. For the second case, this was initially interpreted as positive by IHC, but on review some subtle differences were identified.
    CONCLUSIONS: SDHB immunostaining may be positive in renal cell carcinoma associated to germline SDHB deficiency which have other typical morphological features. Immunohistochemistry interpretation may be complex.
    Keywords:  Clear cell carcinoma; Hereditary renal cancer; SDHB; Succinate dehydrogenase, PGL4 syndrome
  14. Semin Cell Dev Biol. 2019 May 13. pii: S1084-9521(18)30164-2. [Epub ahead of print]
    Kopecka J, Gazzano E, Castella B, Salaroglio IC, Mungo E, Massaia M, Riganti C.
      Mitochondria have been considered for a long time only as the principal source of building blocks and energy upon aerobic conditions. Recently they emerged as key players in cell proliferation, invasion and resistance to therapy. The most aggressive tumors are able to evade the immune-surveillance. Alterations in the mitochondria metabolism either in cancer cells or in host immune system cells are involved in such tumor-induced immune-suppression. This review will focus on the main mitochondrial dysfunctions in tumor and immune cell populations determining immune-resistance, and on the therapies that may target mitochondrial metabolism and restore a powerful anti-tumor immune-activity.
    Keywords:  Mitochondrial metabolism; immunogenic cell death; mitochondrial danger-associated molecular patterns; tumor-induced immune-escape; tumor-induced immune-suppression
  15. Autophagy. 2019 May 16.
    Zheng Y, Wu X, Chen Z, Zhang X.
      Mitophagy is the sole mechanism for neurons to eliminate superfluous or damaged mitochondria. Although the critical implications of mitophagy have been emphasized in a variety of neurological disorders, it remains ambiguous how neurons control the quality of axonal mitochondria. By employing an oxygen-glucose-deprivation and reperfusion (OGD-Rep) model in cultured neurons, our recent results clearly documented the prompt recovery of retrograde transport of axonal mitochondria to neuronal soma. Moreover, by selectively labeling axonal mitochondria, we found that these axonal mitochondria appear in neuronal soma and are eliminated via autophagosomes in priority. This mitochondrial movement from axon to soma has a critical contribution to overall neuronal mitophagy under ischemia. Because forced expression of an anchoring protein, SNPH (Syntaphilin), significantly blocks mitophagy, and aggravates mitochondrial dysfunction and neuronal injury. Conversely, promoted retrograde mitochondrial movement facilitates neuronal mitophagy and attenuates ischemic neuronal demise. In conclusion, we propose stimulating the somatic autophagy of axonal mitochondria after ischemic insults. These findings may provide further insight into how neurons control the mitochondrial quality in pathological conditions and offer novel strategies to cure neurological disorders.
    Keywords:  axon; ischemia; mitochondrial transport; mitophagy; neuron
  16. Nat Commun. 2019 May 17. 10(1): 2213
    Rashid M, van der Horst M, Mentzel T, Butera F, Ferreira I, Pance A, Rütten A, Luzar B, Marusic Z, de Saint Aubain N, Ko JS, Billings SD, Chen S, Abi Daoud M, Hewinson J, Louzada S, Harms PW, Cerretelli G, Robles-Espinoza CD, Patel RM, van der Weyden L, Bakal C, Hornick JL, Arends MJ, Brenn T, Adams DJ.
      Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.
  17. Mitochondrion. 2019 May 14. pii: S1567-7249(19)30046-7. [Epub ahead of print]
    Todkar K, Chikhi L, Germain M.
      Mitochondria are essential organelles required for cellular processes ranging from energy production to cellular differentiation. To perform these functions, mitochondria physically and functionally interact with other organelles such as the endoplasmic reticulum (ER) and endosomes. While the role of ER-mitochondria contact sites is well established, the interaction between mitochondria and endosomes has only recently been reported. These interactions are involved in lipid and ion transfer and potentially play a crucial role in mitochondria quality control and the release of mitochondrial components within extracellular vesicles. Here, we will discuss the current view of mitochondria-endosome interaction, both physically and functionally.
    Keywords:  Endocytosis; Extracellular vesicles; Lysosome; Metabolism; Mitochondria-derived vesicles; Mitochondrial dynamics
  18. Cancer Discov. 2019 May 14.
    Linehan WM, Schmidt LS, Crooks DR, Wei D, Srinivasan R, Lang M, Ricketts CJ.
      Kidney cancer is not a single disease but represents several distinct types of cancer that have defining histologies and genetic alterations and that follow different clinical courses and have different responses to therapy. Mutation of genes associated with kidney cancer, such as VHL, FLCN, TFE3, FH, or SDHB, dysregulates the tumor's responses to changes in oxygen, iron, nutrient, or energy levels. The identification of these varying genetic bases of kidney cancer has increased our understanding of the biology of this cancer, allowing the development of targeted therapies and the appreciation that it is a cancer driven by metabolic alterations.Significance: Kidney cancer is a complex disease composed of different types of cancer that present with different histologies, clinical courses, genetic changes, and responses to therapy. This review describes the known genetic changes within kidney cancer, how they alter tumor metabolism, and how these metabolic changes can be therapeutically targeted.
  19. Nat Commun. 2019 May 17. 10(1): 2205
    Cheng G, Zhang Q, Pan J, Lee Y, Ouari O, Hardy M, Zielonka M, Myers CR, Zielonka J, Weh K, Chang AC, Chen G, Kresty L, Kalyanaraman B, You M.
      Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.
  20. Cell Rep. 2019 May 14. pii: S2211-1247(19)30487-5. [Epub ahead of print]27(7): 2063-2074.e5
    Qiu J, Villa M, Sanin DE, Buck MD, O'Sullivan D, Ching R, Matsushita M, Grzes KM, Winkler F, Chang CH, Curtis JD, Kyle RL, Van Teijlingen Bakker N, Corrado M, Haessler F, Alfei F, Edwards-Hicks J, Maggi LB, Zehn D, Egawa T, Bengsch B, Klein Geltink RI, Jenuwein T, Pearce EJ, Pearce EL.
      Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer.
    Keywords:  T cell exhaustion; T cell hyporesponsiveness; T cells; acetate; acetyl-CoA synthetase; chromatin remodeling; effector functions; tumor immunity; tumor-infiltrating lymphocytes
  21. PLoS Biol. 2019 May;17(5): e3000245
    Murphy JT, Liu H, Ma X, Shaver A, Egan BM, Oh C, Boyko A, Mazer T, Ang S, Khopkar R, Javaheri A, Kumar S, Jiang X, Ory D, Mani K, Matkovich SJ, Kornfeld K, Diwan A.
      Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix-loop-helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30-dependent manner, also demonstrated increased mortality with starvation-refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation-refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation-refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival.
  22. Redox Biol. 2019 May 02. pii: S2213-2317(19)30050-3. [Epub ahead of print]24 101210
    Lee S, Hallis SP, Jung KA, Ryu D, Kwak MK.
      Hypoxia, a common element in the tumor environment, leads to Hypoxia-Inducible Factor-1α (HIF-1α) stabilization to modulate cellular metabolism as an adaptive response. In a previous study, we showed that inhibition of the nuclear factor erythroid 2-like-2 (NFE2L2; NRF2), a master regulator of many genes coping with electrophilic and oxidative stress, elevated the level of miR-181c and induced mitochondrial dysfunction in colon cancer cells. In this study, we demonstrate that NRF2-silencing hindered HIF-1α accumulation in hypoxic breast cancer cells and subsequently suppressed hypoxia-inducible expression of glycolysis-associated glucose transporter-1, hexokinase-2, pyruvate dehydrogenase kinase-1, and lactate dehydrogenase A. HIF-1α dysregulation in NRF2-silenced cancer cells was associated with miR-181c elevation. Overexpression of miR-181c in breast cancer cells blocked HIF-1α accumulation and diminished hypoxia-inducible levels of glycolysis enzymes, whereas the inhibition of miR-181c in NRF2-silenced cells restored HIF-1α accumulation. In a subsequent metabolomic analysis, hypoxic incubation increased the levels of metabolites involved in glycolysis and activated the pentose phosphate pathway (PPP) in control cells. However, these elevations were less pronounced in NRF2-silenced cells. In particular, hypoxic incubation increased the levels of amino acids, which implies a shift to catabolic metabolism, and the increased levels were higher in control cells than in NRF2-silenced cells. Concurrently, hypoxia activated BCL2 interacting protein 3 (BNIP3)-mediated autophagy in the control cells and miR-181c was found to be involved in this autophagy activation. Taken together, these results show that hypoxia-induced metabolic changes to glycolysis, the PPP, and autophagy are inhibited by NRF2-silencing through miR-181c-mediated HIF-1α dysregulation. Therefore, targeting NRF2/miR-181c could be an effective strategy to counteract HIF-1α-orchestrated metabolic adaptation of hypoxic cancer cells.
    Keywords:  Autophagy; HIF-1α; Hypoxia; Metabolism; Metabolome; NFE2L2/NRF2
  23. Biochim Biophys Acta Mol Basis Dis. 2019 May 14. pii: S0925-4439(19)30167-X. [Epub ahead of print]
    Yang M, Linn BS, Zhang Y, Ren J.
      Ischemia-reperfusion injury (IR injury), produced by initial interruption and subsequent restoration of organ blood flow, is an important clinical dilemma accompanied by various cardiac reperfusion strategies following acute myocardial infarction (AMI). Although the restored blood flow is necessary for oxygen and nutrient supply, reperfusion often results in pathological sequelae leading to elevated ischemic damage. Among various theories postulated for IR injury including vascular leakage, oxidative stress, leukocyte entrapment, inflammation and apoptosis, mitochondrial dysfunction plays an essential role in mediating pathophysiological processes with recent evidence depicting a pivotal role for impaired mitophagy in mitochondrial injury. Given the critical role for mitophagy in mitochondrial quality control and the recent reports supporting a tie between mitophagy and IR injury, this review will revisit the contemporary understanding of mitophagy in the regulation of cardiac homeostasis and update recent progresses with regards to mitophagy and cardiac IR injury. We hope to establish a role for mitophagy as a potential therapeutic target in the management of IR injury.
    Keywords:  Autophagy; Hypoxia-reoxygenation; Mitochondrial dynamics; Mitochondrial fusion and fission; Mitochondrial quality control; Mitochondrial turnover
  24. Cancers (Basel). 2019 May 15. pii: E675. [Epub ahead of print]11(5):
    Choi BH, Coloff JL.
      Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy.
    Keywords:  arginine; asparagine; aspartate; cancer; cysteine; glutamate; glutamine; glycine; proline; serine
  25. Dev Cell. 2019 May 06. pii: S1534-5807(19)30279-5. [Epub ahead of print]
    Molaei M, Vandehoef C, Karpac J.
      Metabolic and innate immune signaling pathways have co-evolved to elicit coordinated responses. However, dissecting the integration of these ancient signaling mechanisms remains a challenge. Using Drosophila, we uncovered a role for the innate immune transcription factor nuclear factor κB (NF-κB)/Relish in governing lipid metabolism during metabolic adaptation to fasting. We found that Relish is required to restrain fasting-induced lipolysis, and thus conserve cellular triglyceride levels during metabolic adaptation, through specific repression of ATGL/Brummer lipase gene expression in adipose (fat body). Fasting-induced changes in Brummer expression and, consequently, triglyceride metabolism are adjusted by Relish-dependent attenuation of Foxo transcriptional activation function, a critical metabolic transcription factor. Relish limits Foxo function by influencing fasting-dependent histone deacetylation and subsequent chromatin modifications within the Bmm locus. These results highlight that the antagonism of Relish and Foxo functions are crucial in the regulation of lipid metabolism during metabolic adaptation, which may further influence the coordination of innate immune-metabolic responses.
    Keywords:  ATGL; Bmm; Drosophila; Foxo; NF-κB; Relish; histone acetylation; innate immune; lipid metabolism; metabolic adaptation
  26. J Biol Chem. 2019 May 16. pii: jbc.RA118.006443. [Epub ahead of print]
    Hurst S, Baggett A, Csordas G, Sheu SS.
      The mitochondrial m-AAA protease Spastic Paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca2+ induced mPTP opening. However, this occurs independently of Cyclophilin D (Cyclosporine A insensitive) rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. We found that SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter (MCU) and MCU processing regulates higher order MCU-complex formation. The results suggest that SPG7 does not constitute a core component of the mPTP but can modulate mPTP through regulation of the basal mitochondrial Ca2+ concentration.
    Keywords:  Mitochondrial Calcium Uniporter; Spastic Paraplegia 7; calcium; cyclophilin D; mitochondrial permeability transition (MPT); protein processing; protein turnover
  27. Cell Death Dis. 2019 May 15. 10(6): 376
    Slobodnyuk K, Radic N, Ivanova S, Llado A, Trempolec N, Zorzano A, Nebreda AR.
      Apoptosis and senescence are two mutually exclusive cell fate programs that can be activated by stress. The factors that instruct cells to enter into senescence or apoptosis are not fully understood, but both programs can be regulated by the stress kinase p38α. Using an inducible system that specifically activates this pathway, we show that sustained p38α activation suffices to trigger massive autophagosome formation and to enhance the basal autophagic flux. This requires the concurrent effect of increased mitochondrial reactive oxygen species production and the phosphorylation of the ULK1 kinase on Ser-555 by p38α. Moreover, we demonstrate that macroautophagy induction by p38α signaling determines that cancer cells preferentially enter senescence instead of undergoing apoptosis. In agreement with these results, we present evidence that the induction of autophagy by p38α protects cancer cells from chemotherapy-induced apoptosis by promoting senescence. Our results identify a new mechanism of p38α-regulated basal autophagy that controls the fate of cancer cells in response to stress.
  28. PLoS One. 2019 ;14(5): e0216553
    Che L, Yang X, Ge C, El-Amouri SS, Wang QE, Pan D, Herzog TJ, Du C.
      Autophagy is an intracellular catabolic system. It delivers cellular components to lysosomes for degradation and supplies nutrients that promote cell survival under stress conditions. Although much is known regarding starvation-induced autophagy, the regulation of autophagy by cellular energy level is less clear. BRUCE is an ubiquitin conjugase and ligase with multi-functionality. It has been reported that depletion of BRUCE inhibits starvation-induced autophagy by blockage of the fusion step. Herein we report a new function for BRUCE in the dual regulation of autophagy and cellular energy. Depletion of BRUCE alone (without starvation) in human osteosarcoma U2OS cells elevated autophagic activity as indicted by the increased LC3B-II protein and its autophagic puncta as well as further increase of both by chloroquine treatment. Such elevation results from enhanced induction of autophagy since the numbers of both autophagosomes and autolysosomes were increased, and recruitment of ATG16L onto the initiating membrane structure phagophores was increased. This concept is further supported by elevated lysosomal enzyme activities. In contrast to starvation-induced autophagy, BRUCE depletion did not block fusion of autophagosomes with lysosomes as indicated by increased lysosomal cleavage of the GFP-LC3 fusion protein. Mechanistically, BRUCE depletion lowered the cellular energy level as indicated by both a higher ratio of AMP/ATP and the subsequent activation of the cellular energy sensor AMPK (pThr-172). The lower energy status co-occurred with AMPK-specific phosphorylation and activation of the autophagy initiating kinase ULK1 (pSer-555). Interestingly, the higher autophagic activity by BRUCE depletion is coupled with enhanced cisplatin resistance in human ovarian cancer PEO4 cells. Taken together, BRUCE depletion promotes induction of autophagy by lowering cellular energy and activating the AMPK-ULK1-autophagy axis, which could contribute to ovarian cancer chemo-resistance. This study establishes a BRUCE-AMPK-ULK1 axis in the regulation of energy metabolism and autophagy, as well as provides insights into cancer chemo-resistance.
  29. Neoplasia. 2019 May 08. pii: S1476-5586(19)30091-0. [Epub ahead of print]21(6): 615-626
    Sharick JT, Jeffery JJ, Karim MR, Walsh CM, Esbona K, Cook RS, Skala MC.
      Heterogeneous populations within a tumor have varying metabolic profiles, which can muddle the interpretation of bulk tumor imaging studies of treatment response. Although methods to study tumor metabolism at the cellular level are emerging, these methods provide a single time point "snapshot" of tumor metabolism and require a significant time and animal burden while failing to capture the longitudinal metabolic response of a single tumor to treatment. Here, we investigated a novel method for longitudinal, single-cell tracking of metabolism across heterogeneous tumor cell populations using optical metabolic imaging (OMI), which measures autofluorescence of metabolic coenzymes as a report of metabolic activity. We also investigated whether in vivo cellular metabolic heterogeneity can be accurately captured using tumor-derived three-dimensional organoids in a genetically engineered mouse model of breast cancer. OMI measurements of response to paclitaxel and the phosphatidylinositol-3-kinase inhibitor XL147 in tumors and organoids taken at single cell resolution revealed parallel shifts in metaboltruic heterogeneity. Interestingly, these previously unappreciated heterogeneous metabolic responses in tumors and organoids could not be attributed to tumor cell fate or varying leukocyte content within the microenvironment, suggesting that heightened metabolic heterogeneity upon treatment is largely due to heterogeneous metabolic shifts within tumor cells. Together, these studies show that OMI revealed remarkable heterogeneity in response to treatment, which could provide a novel approach to predict the presence of potentially unresponsive tumor cell subpopulations lurking within a largely responsive bulk tumor population, which might otherwise be overlooked by traditional measurements.
  30. Diabetes. 2019 May 14. pii: db190088. [Epub ahead of print]
    Koh JH, Johnson ML, Dasari S, LeBrasseur NK, Vuckovic I, Henderson GC, Cooper SA, Manjunatha S, Ruegsegger GN, Shulman GI, Lanza IR, Nair KS.
      Diet induced insulin resistance (IR) adversely affects human health and life span. We show that muscle specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high fat diet (HFD)-induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce accumulation IR-related carnitines and ceramides. TFAM also increased pAMPK expression explaining enhanced PGC-1α, and PPARβ and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.
  31. J Clin Invest. 2019 May 13. pii: 124613. [Epub ahead of print]130
    Singer BD, Chandel NS.
      Immune cell populations determine the balance between ongoing damage and repair following tissue injury. Cells responding to a tissue-damaged environment have significant bioenergetic and biosynthetic needs. In addition to supporting these needs, metabolic pathways govern the function of pro-repair immune cells, including regulatory T cells and tissue macrophages. In this Review, we explore how specific features of the tissue-damaged environment such as hypoxia, oxidative stress, and nutrient depletion serve as metabolic cues to promote or impair the reparative functions of immune cell populations. Hypoxia, mitochondrial DNA stress, and altered redox balance each contribute to mechanisms regulating the response to tissue damage. For example, hypoxia induces changes in regulatory T cell and macrophage metabolic profiles, including generation of 2-hydroxyglutarate, which inhibits demethylase reactions to modulate cell fate and function. Reactive oxygen species abundant in oxidative environments cause damage to mitochondrial DNA, initiating signaling pathways that likewise control pro-repair cell function. Nutrient depletion following tissue damage also affects pro-repair cell function through metabolic signaling pathways, specifically those sensitive to the redox state of the cell. The study of immunometabolism as an immediate sensor and regulator of the tissue-damaged environment provides opportunities to consider mechanisms that facilitate healthy repair of tissue injury.
  32. Cancer Res. 2019 May 14. pii: canres.2414.2018. [Epub ahead of print]
    Kennedy BE, Murphy JP, Clements DR, Konda P, Holay N, Kim Y, Pathak GP, Giacomantonio MA, El Hiani Y, Gujar S.
      Oncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here we investigated whether cancer cell metabolism defines its susceptibility to OV, and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry-based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus. In particular, reovirus infection accentuated Warburg-like metabolic perturbations in cell lines relatively resistant to oncolysis. These metabolic changes were facilitated by oxidative stress-induced inhibitory phosphorylation of pyruvate dehydrogenase (PDH) that impaired the routing of pyruvate into the TCA cycle and established a metabolic state unsupportive of OV replication. From the therapeutic perspective, reactivation of PDH in cancer cells that were weakly sensitive for reovirus, either through PDH kinase (PDK) inhibitors dichloroacetate and AZD7545 or shRNA-specific depletion of PDK1, enhanced the efficacy of reovirus-induced oncolysis in vitro and in vivo. These findings identify targeted metabolic reprogramming as a possible combination strategy to enhance the antitumour effects of OV in clinics.
  33. Cancers (Basel). 2019 May 16. pii: E678. [Epub ahead of print]11(5):
    Combs JA, DeNicola GM.
      The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of intracellular cysteine to support cellular processes. In contrast, many cancers require exogeneous cystine for proliferation and viability. Herein, we review how the cystine transporter, xCT, and exogenous cystine fuel cancer cell proliferation and the mechanisms that regulate xCT expression and activity. Further, we discuss the potential contribution of additional sources of cysteine to the cysteine pool and what is known about the essentiality of these processes in cancer cells. Finally, we discuss whether cyst(e)ine dependency and associated metabolic alterations represent therapeutically targetable metabolic vulnerabilities.
    Keywords:  CBS; CSE; GGT; cystathionine; cysteine; cystine; glutathione; macropinocytosis; transsulfuration; xCT
  34. Neuro Oncol. 2019 Apr 26. pii: noz072. [Epub ahead of print]
    Dardaud LM, Bris C, Desquiret-Dumas V, Boisselier B, Tabouret E, Mokhtari K, Figarella-Branger D, Rousseau A, Procaccio V.
    Keywords:  glioblastoma; mitochondrial genome; mtDNA copy number; prognosis and survival; young adults
  35. Nephrology (Carlton). 2019 May 17.
    Xu C, Kasimumali A, Guo X, Lu R, Xie K, Zhu M, Qian Y, Chen X, Pang H, Wang Q, Fan Z, Dai H, Mou S, Ni Z, Gu L.
      AIM: Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post-translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle.METHODS: Twenty patients with stage 4-5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other 8 non-CKD surgical subjects' muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real-time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology.
    RESULTS: CKD patients had lower HGS than non-CKD subjects, and HGS was correlated with gender, age, hemoglobin and albumin. Mitochondria were decreased in end-stage renal disease (ESRD) patients muscle. Mfn-1 expression and phospho-Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phosphor-PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated CONCLUSION: Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients. This article is protected by copyright. All rights reserved.
    Keywords:  Drp1; Handgrip strength; Mfn-1; PGC-1α; pyruvate dehydrogenase
  36. Br J Cancer. 2019 May 16.
    Munir R, Lisec J, Swinnen JV, Zaidi N.
      Cancer cells are often exposed to a metabolically challenging environment with scarce availability of oxygen and nutrients. This metabolic stress leads to changes in the balance between the endogenous synthesis and exogenous uptake of fatty acids, which are needed by cells for membrane biogenesis, energy production and protein modification. Alterations in lipid metabolism and, consequently, lipid composition have important therapeutic implications, as they affect the survival, membrane dynamics and therapy response of cancer cells. In this article, we provide an overview of recent insights into the regulation of lipid metabolism in cancer cells under metabolic stress and discuss how this metabolic adaptation helps cancer cells thrive in a harsh tumour microenvironment.
  37. Cancer Res. 2019 May 14. pii: canres.3541.2018. [Epub ahead of print]
    Xia Y, Ye B, Ding J, Yu Y, Alptekin A, Thangaraju M, Prasad PD, Ding ZC, Park EJ, Choi JH, Gao B, Fiehn O, Yan C, Dong Z, Zha Y, Ding HF.
      MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activating ATF4 mRNA expression and ATF4 stabilizing MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy.
  38. J Zhejiang Univ Sci B. 2019 May;20(5): 437-448
    Nie H, Yi W.
      O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification occurring on myriad proteins in the cell nucleus, cytoplasm, and mitochondria. The donor sugar for O-GlcNAcylation, uridine-diphosphate N-acetylglucosamine (UDP-GlcNAc), is synthesized from glucose through the hexosamine biosynthetic pathway (HBP). The recycling of O-GlcNAc on proteins is mediated by two enzymes in cells-O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of O-GlcNAc, respectively. O-GlcNAcylation is involved in a number of important cell processes including transcription, translation, metabolism, signal transduction, and apoptosis. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, neurodegenerative diseases, and cardiovascular diseases. A better understanding of the roles of O-GlcNAcylation in physiopathological processes would help to uncover novel avenues for therapeutic intervention. The aim of this review is to discuss the recent updates on the mechanisms and impacts of O-GlcNAcylation on these diseases, and its potential as a new clinical target.
    Keywords:  O-GlcNAcylation; Cancer; Diabetes; Neurodegenerative disease; Cardiovascular disease
  39. FASEB J. 2019 May 14. fj201802842RR
    Biswas D, Duffley L, Pulinilkunnil T.
      Beyond their contribution as fundamental building blocks of life, branched-chain amino acids (BCAAs) play a critical role in physiologic and pathologic processes. Importantly, BCAAs are associated with insulin resistance, obesity, cardiovascular disease, and genetic disorders. However, several metabolome-wide studies in recent years could not attribute alterations in systemic BCAAs as the sole driver of endocrine perturbations, suggesting that a snapshot of global BCAA changes does not always reveal the underlying modifications. Because enzymes catabolizing BCAAs have a unique distribution, it is plausible that the tissue-specific roles of BCAA-catabolic enzymes could precipitate changes in systemic BCAA levels, flux, and action. We review the genetic and pharmacological approaches dissecting the role of BCAA-catabolic enzyme dysfunctions. We summarized emerging evidence on BCAA metabolic intermediates, tissue specificity of BCAA-catabolizing enzymes, and crosstalk between different metabolites in driving metabolic maladaptation in health and pathology. This review substantiates the understanding that tissue-specific dysfunction of the BCAA-catabolic enzymes and accumulating intermediary metabolites could act as better surrogates of metabolic imbalances, highlighting the biochemical communication among the nutrient triad of BCAAs, glucose, and fatty acid.-Biswas, D., Duffley, L., Pulinilkunnil, T. Role of branched-chain amino acid-catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis.
    Keywords:  BCAT; BCKA; BCKDH; KLF15; PPM1K
  40. Blood. 2019 May 17. pii: blood.2019898114. [Epub ahead of print]
    Jones CL, Stevens BM, D'Alessandro A, Culp-Hill R, Reisz JA, Pei S, Gustafson A, Khan N, DeGregori J, Pollyea DA, Jordan CT.
      We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from acute myeloid leukemia (AML) patients. More recently, we demonstrated that LSCs in de novo AML patients rely on amino acid metabolism to drive oxidative phosphorylation. Notably, while overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP and leading to LSC death. Given the role of cysteine in driving LSC energy production we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism and that targeting this axis may represent a useful therapeutic strategy.
  41. Nat Commun. 2019 05 13. 10(1): 2130
    Dabral S, Muecke C, Valasarajan C, Schmoranzer M, Wietelmann A, Semenza GL, Meister M, Muley T, Seeger-Nukpezah T, Samakovlis C, Weissmann N, Grimminger F, Seeger W, Savai R, Pullamsetti SS.
      Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.
  42. Nat Rev Cancer. 2019 May 17.
    Friedmann Angeli JP, Krysko DV, Conrad M.
      Ferroptosis is a recently recognized cell death modality that is morphologically, biochemically and genetically distinct from other forms of cell death and that has emerged to play an important role in cancer biology. Recent discoveries have highlighted the metabolic plasticity of cancer cells and have provided intriguing insights into how metabolic rewiring is a critical event for the persistence, dedifferentiation and expansion of cancer cells. In some cases, this metabolic reprogramming has been linked to an acquired sensitivity to ferroptosis, thus opening up new opportunities to treat therapy-insensitive tumours. However, it is not yet clear what metabolic determinants are critical for therapeutic resistance and evasion of immune surveillance. Therefore, a better understanding of the processes that regulate ferroptosis sensitivity should ultimately aid in the discovery of novel therapeutic strategies to improve cancer treatment. In this Perspectives article, we provide an overview of the known mechanisms that regulate sensitivity to ferroptosis in cancer cells and how the modulation of metabolic pathways controlling ferroptosis might reshape the tumour niche, leading to an immunosuppressive microenvironment that promotes tumour growth and progression.