bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒07‒12
fifty-six papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Nat Rev Cancer. 2020 Jul 06.
    Leone RD, Powell JD.
      Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.
    DOI:  https://doi.org/10.1038/s41568-020-0273-y
  2. Nature. 2020 Jul 08.
    Mok BY, de Moraes MH, Zeng J, Bosch DE, Kotrys AV, Raguram A, Hsu F, Radey MC, Peterson SB, Mootha VK, Mougous JD, Liu DR.
      Bacterial toxins represent a vast reservoir of biochemical diversity that can be repurposed for biomedical applications. Such proteins include a group of predicted interbacterial toxins of the deaminase superfamily, members of which have found application in gene-editing techniques1,2. Because previously described cytidine deaminases operate on single-stranded nucleic acids3, their use in base editing requires the unwinding of double-stranded DNA (dsDNA)-for example by a CRISPR-Cas9 system. Base editing within mitochondrial DNA (mtDNA), however, has thus far been hindered by challenges associated with the delivery of guide RNA into the mitochondria4. As a consequence, manipulation of mtDNA to date has been limited to the targeted destruction of the mitochondrial genome by designer nucleases9,10.Here we describe an interbacterial toxin, which we name DddA, that catalyses the deamination of cytidines within dsDNA. We engineered split-DddA halves that are non-toxic and inactive until brought together on target DNA by adjacently bound programmable DNA-binding proteins. Fusions of the split-DddA halves, transcription activator-like effector array proteins, and a uracil glycosylase inhibitor resulted in RNA-free DddA-derived cytosine base editors (DdCBEs) that catalyse C•G-to-T•A conversions in human mtDNA with high target specificity and product purity. We used DdCBEs to model a disease-associated mtDNA mutation in human cells, resulting in changes in respiration rates and oxidative phosphorylation. CRISPR-free DdCBEs enable the precise manipulation of mtDNA, rather than the elimination of mtDNA copies that results from its cleavage by targeted nucleases, with broad implications for the study and potential treatment of mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41586-020-2477-4
  3. Nature. 2020 Jul 08.
    Jimenez-Blasco D, Busquets-Garcia A, Hebert-Chatelain E, Serrat R, Vicente-Gutierrez C, Ioannidou C, Gómez-Sotres P, Lopez-Fabuel I, Resch-Beusher M, Resel E, Arnouil D, Saraswat D, Varilh M, Cannich A, Julio-Kalajzic F, Bonilla-Del Río I, Almeida A, Puente N, Achicallende S, Lopez-Rodriguez ML, Jollé C, Déglon N, Pellerin L, Josephine C, Bonvento G, Panatier A, Lutz B, Piazza PV, Guzmán M, Bellocchio L, Bouzier-Sore AK, Grandes P, Bolaños JP, Marsicano G.
      Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses1-5. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors5-7. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB1) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB1 receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.
    DOI:  https://doi.org/10.1038/s41586-020-2470-y
  4. Nature. 2020 Jul 08.
    Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS, Werner M, Kihshen H, Reczek CR, Weinberg SE, Gao P, Steinert EM, Piseaux R, Budinger GRS, Chandel NS.
      The mitochondrial electron transport chain (ETC) is necessary for tumour growth1-6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7-9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP-that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)-an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX)12, which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis (LbNOX)13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity.
    DOI:  https://doi.org/10.1038/s41586-020-2475-6
  5. Cardiovasc Drugs Ther. 2020 Jul 09.
    Prag HA, Pala L, Kula-Alwar D, Mulvey JF, Luping D, Beach TE, Booty LM, Hall AR, Logan A, Sauchanka V, Caldwell ST, Robb EL, James AM, Xu Z, Saeb-Parsy K, Hartley RC, Murphy MP, Krieg T.
      PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters.METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction.
    RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion.
    CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.
    Keywords:  Drug delivery; Ischemia/reperfusion injury; Malonate; Mitochondria; Succinate
    DOI:  https://doi.org/10.1007/s10557-020-07033-6
  6. J Biol Chem. 2020 Jul 07. pii: jbc.REV119.007624. [Epub ahead of print]
    Wang YP, Li JT, Qu J, Yin M, Lei QY.
      Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate (2HG) provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells sense and remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition (EMT), differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in-depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer.
    Keywords:  Metabolite; Sensing; Signaling; cancer; metabolic disease; metabolic regulation; metabolomics; oncometabolite; signaling
    DOI:  https://doi.org/10.1074/jbc.REV119.007624
  7. iScience. 2020 Jun 20. pii: S2589-0042(20)30482-X. [Epub ahead of print]23(7): 101295
    Bose HS, Marshall B, Debnath DK, Perry EW, Whittal RM.
      The first steroidogenic enzyme, cytochrome P450-side-chain-cleavage (SCC), requires electron transport chain (ETC) complexes III and IV to initiate steroid metabolic processes for mammalian survival. ETC complex II, containing succinate dehydrogenase (quinone), acts with the TCA cycle and has no proton pumping capacity. We show that complex II is required for SCC activation through the proton pump, generating an intermediate state for addition of phosphate by succinate. Phosphate anions in the presence of succinate form a stable mitochondrial complex with higher enthalpy (-ΔH) and enhanced activity. Inhibition of succinate action prevents SCC processing at the intermediate state and ablates activity and mitochondrial protein network. This is the first report directly showing that a protein intermediate state is activated by succinate, facilitating the ETC complex II to interact with complexes III and IV for continued mitochondrial metabolic process, suggesting complex II is essential for steroid metabolism regulation.
    Keywords:  Biochemistry; Biological Sciences; Molecular Biology
    DOI:  https://doi.org/10.1016/j.isci.2020.101295
  8. PLoS One. 2020 ;15(7): e0232072
    Cohen EB, Geck RC, Toker A.
      The vasculature within a tumor is highly disordered both structurally and functionally. Endothelial cells that comprise the vasculature are poorly connected causing vessel leakage and exposing the endothelium to a hypoxic microenvironment. Therefore, most anti-angiogenic therapies are generally inefficient and result in acquired resistance to increased hypoxia due to elimination of the vasculature. Recent studies have explored the efficacy of targeting metabolic pathways in tumor cells in combination with anti-angiogenic therapy. However, the metabolic alterations of endothelial cells in response to hypoxia have been relatively unexplored. Here, we measured polar metabolite levels in microvascular endothelial cells exposed to short- and long-term hypoxia with the goal of identifying metabolic vulnerabilities that can be targeted to normalize tumor vasculature and improve drug delivery. We found that many amino acid-related metabolites were altered by hypoxia exposure, especially within alanine-aspartate-glutamate, serine-threonine, and cysteine-methionine metabolism. Additionally, there were significant changes in de novo pyrimidine synthesis as well as glutathione and taurine metabolism. These results provide key insights into the metabolic alterations that occur in endothelial cells in response to hypoxia, which serve as a foundation for future studies to develop therapies that lead to vessel normalization and more efficient drug delivery.
    DOI:  https://doi.org/10.1371/journal.pone.0232072
  9. Int Immunol. 2020 Jul 05. pii: dxaa046. [Epub ahead of print]
    Kumar A, Chamoto K.
      Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming patient unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address the issue of the unresponsiveness of some patients. Cancer cells render their microenvironment immunosuppressive, driving T cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers of immune checkpoint inhibitors.
    Keywords:  biomarker; combination therapy; energy metabolism; immune checkpoint; mitochondria
    DOI:  https://doi.org/10.1093/intimm/dxaa046
  10. Mol Genet Metab. 2020 Jun 27. pii: S1096-7192(20)30150-5. [Epub ahead of print]
    Uittenbogaard M, Chiaramello A.
      Maternally inherited mitochondrial respiratory disorders are rare, progressive, and multi-systemic diseases that remain intractable, with no effective therapeutic interventions. Patients share a defective oxidative phosphorylation pathway responsible for mitochondrial ATP synthesis, in most cases due to pathogenic mitochondrial variants transmitted from mother to child or to a rare de novo mutation or large-scale deletion of the mitochondrial genome. The clinical diagnosis of these mitochondrial diseases is difficult due to exceptionally high clinical variability, while their genetic diagnosis has improved with the advent of next-generation sequencing. The mechanisms regulating the penetrance of the mitochondrial variants remain unresolved with the patient's nuclear background, epigenomic regulation, heteroplasmy, mitochondrial haplogroups, and environmental factors thought to act as rheostats. The lack of animal models mimicking the phenotypic manifestations of these disorders has hampered efforts toward curative therapies. Patient-derived cellular paradigms provide alternative models for elucidating the pathogenic mechanisms and screening pharmacological small molecules to enhance mitochondrial function. Recent progress has been made in designing promising approaches to curtail the negative impact of dysfunctional mitochondria and alleviate clinical symptoms: 1) boosting mitochondrial biogenesis; 2) shifting heteroplasmy; 3) reprogramming metabolism; and 4) administering hypoxia-based treatment. Here, we discuss their varying efficacies and limitations and provide an outlook on their therapeutic potential and clinical application.
    Keywords:  Hypoxia-directed intervention; Metabolic reprogramming; Mitochondrial genetics; Mitochondrial genome editing; Mitochondrial homeostasis; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.ymgme.2020.06.011
  11. EMBO Rep. 2020 Jul 09. e49898
    Zhang J, Andersen JP, Sun H, Liu X, Sonenberg N, Nie J, Shi Y.
      Nutrient sensing by the mTOR complex 1 (mTORC1) requires its translocation to the lysosomal membrane. Upon amino acids removal, mTORC1 becomes cytosolic and inactive, yet its precise subcellular localization and the mechanism of inhibition remain elusive. Here, we identified Aster-C as a negative regulator of mTORC1 signaling. Aster-C earmarked a special rough ER subdomain where it sequestered mTOR together with the GATOR2 complex to prevent mTORC1 activation during nutrient starvation. Amino acids stimulated rapid disassociation of mTORC1 from Aster-C concurrently with assembly of COP I vesicles which escorted mTORC1 to the lysosomal membrane. Consequently, ablation of Aster-C led to spontaneous activation of mTORC1 and dissociation of TSC2 from lysosomes, whereas inhibition of COP I vesicle biogenesis or actin dynamics prevented mTORC1 activation. Together, these findings identified Aster-C as a missing link between lysosomal trafficking and mTORC1 activation by revealing an unexpected role of COP I vesicles in mTORC1 signaling.
    Keywords:  ARF1; COP I; GRAMD1C; lysosomes; mTORC1
    DOI:  https://doi.org/10.15252/embr.201949898
  12. Aging Cell. 2020 Jul 06. e13187
    Liang W, Moyzis AG, Lampert MA, Diao RY, Najor RH, Gustafsson ÅB.
      Advancing age is a major risk factor for developing heart disease, and the biological processes contributing to aging are currently under intense investigation. Autophagy is an important cellular quality control mechanism that is reduced in tissues with age but the molecular mechanisms underlying the age-associated defects in autophagy remain poorly characterized. Here, we have investigated how the autophagic process is altered in aged mouse hearts. We report that autophagic activity is reduced in aged hearts due to a reduction in autophagosome formation. Gene expression profile analysis to evaluate changes in autophagy regulators uncovered a reduction in Atg9b transcript and protein levels. Atg9 proteins are critical in delivering membrane to the growing autophagosome, and siRNA knockdown of Atg9b in cells confirmed a reduction in autophagosome formation. Autophagy is also the main pathway involved in eliminating dysfunctional mitochondria via a process known as mitophagy. The E3 ubiquitin ligase Parkin plays a key role in labeling mitochondria for mitophagy. We also found increased levels of Parkin-positive mitochondria in the aged hearts, an indication that they have been labeled for mitophagy. In contrast, Nrf1, a major transcriptional regulator of mitochondrial biogenesis, was significantly reduced in aged hearts. Additionally, our data showed reduced Drp1-mediated mitochondrial fission and formation of enlarged mitochondria in the aged heart. Overall, our findings suggest that cardiac aging is associated with reduced autophagosome number, decreased mitochondrial turnover, and formation of megamitochondria.
    Keywords:  Atg9; Parkin; aging; autophagy; heart; mitochondria; mitophagy
    DOI:  https://doi.org/10.1111/acel.13187
  13. Cell Metab. 2020 Jul 02. pii: S1550-4131(20)30311-9. [Epub ahead of print]
    Kelly B, Pearce EL.
      Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined, but they contribute to a host of other intracellular metabolic pathways, including ATP generation, nucleotide synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend on such pathways to acquire energy and biomass and to reprogram their metabolism upon activation to support growth, proliferation, and effector functions. Amino acid metabolism plays a key role in this metabolic rewiring, and it supports various immune cell functions beyond increased protein synthesis. Here, we review the mechanisms by which amino acid metabolism promotes immune cell function, and how these processes could be targeted to improve immunity in pathological conditions.
    Keywords:  ▪▪▪
    DOI:  https://doi.org/10.1016/j.cmet.2020.06.010
  14. Front Physiol. 2020 ;11 690
    Moore TM, Lin AJ, Strumwasser AR, Cory K, Whitney K, Ho T, Ho T, Lee JL, Rucker DH, Nguyen CQ, Yackly A, Mahata SK, Wanagat J, Stiles L, Turcotte LP, Crosbie RH, Zhou Z.
      Duchenne muscular dystrophy (DMD) is characterized by rapid wasting of skeletal muscle. Mitochondrial dysfunction is a well-known pathological feature of DMD. However, whether mitochondrial dysfunction occurs before muscle fiber damage in DMD pathology is not well known. Furthermore, the impact upon heterozygous female mdx carriers (mdx/+), who display dystrophin mosaicism, has received little attention. We hypothesized that dystrophin deletion leads to mitochondrial dysfunction, and that this may occur before myofiber necrosis. As a secondary complication to mitochondrial dysfunction, we also hypothesized metabolic abnormalities prior to the onset of muscle damage. In this study, we detected aberrant mitochondrial morphology, reduced cristae number, and large mitochondrial vacuoles from both male and female mdx mice prior to the onset of muscle damage. Furthermore, we systematically characterized mitochondria during disease progression starting before the onset of muscle damage, noting additional changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice that were exacerbated with high-fat diet feeding. Lastly, inhibition of the strong autophagic program observed in adolescent mdx male mice via administration of the autophagy inhibitor leupeptin did not improve skeletal muscle pathology. These results are in line with previous data and suggest that before the onset of myofiber necrosis, mitochondrial and metabolic abnormalities are present within the mdx mouse.
    Keywords:  Duchenne muscular dystrophy; autophagy; dystrophin; metabolism; mitochondria; muscular dystrophy; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2020.00690
  15. Biomolecules. 2020 Jul 04. pii: E998. [Epub ahead of print]10(7):
    Bonora M, Patergnani S, Ramaccini D, Morciano G, Pedriali G, Kahsay AE, Bouhamida E, Giorgi C, Wieckowski MR, Pinton P.
      Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation.
    Keywords:  Cyclosporin A; apoptosis; cancer; ischemia/reperfusion; mitochondrial permeability transition; necrosis; neurodegeneration
    DOI:  https://doi.org/10.3390/biom10070998
  16. Biomolecules. 2020 Jul 07. pii: E1008. [Epub ahead of print]10(7):
    Horten P, Colina-Tenorio L, Rampelt H.
      : Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.
    Keywords:  TIM chaperones; TIM22; TOM; metabolite transport; mitochondrial biogenesis; mitochondrial carrier; mitochondrial pyruvate carrier; protein translocation; sideroflexin
    DOI:  https://doi.org/10.3390/biom10071008
  17. EMBO Rep. 2020 Jul 06. e201949801
    Han S, Jeong YY, Sheshadri P, Su X, Cai Q.
      Synaptic mitochondria are particularly vulnerable to physiological insults, and defects in synaptic mitochondria are linked to early pathophysiology of Alzheimer's disease (AD). Mitophagy, a cargo-specific autophagy for elimination of dysfunctional mitochondria, constitutes a key quality control mechanism. However, how mitophagy ensures synaptic mitochondrial integrity remains largely unknown. Here, we reveal Rheb and Snapin as key players regulating mitochondrial homeostasis at synapses. Rheb initiates mitophagy to target damaged mitochondria for autophagy, whereas dynein-Snapin-mediated retrograde transport promotes clearance of mitophagosomes from synaptic terminals. We demonstrate that synaptic accumulation of mitophagosomes is a feature in AD-related mutant hAPP mouse brains, which is attributed to increased mitophagy initiation coupled with impaired removal of mitophagosomes from AD synapses due to defective retrograde transport. Furthermore, while deficiency in dynein-Snapin-mediated retrograde transport recapitulates synaptic mitophagy stress and induces synaptic degeneration, elevated Snapin expression attenuates mitochondrial defects and ameliorates synapse loss in AD mouse brains. Taken together, our study provides new insights into mitophagy regulation of synaptic mitochondrial integrity, establishing a foundation for mitigating AD-associated mitochondria deficits and synaptic damage through mitophagy enhancement.
    Keywords:  Alzheimer's; mitophagosome; retrograde transport; synaptic mitochondrial deficits; synaptic mitophagy
    DOI:  https://doi.org/10.15252/embr.201949801
  18. Cell Metab. 2020 Jun 30. pii: S1550-4131(20)30309-0. [Epub ahead of print]
    Jensen-Cody SO, Flippo KH, Claflin KE, Yavuz Y, Sapouckey SA, Walters GC, Usachev YM, Atasoy D, Gillum MP, Potthoff MJ.
      Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.
    Keywords:  FGF21; PVN; VMH; brain; glucose sensing; hepatokine; hypothalamus; liver; macronutrient; sugar intake; sweet-taste preference
    DOI:  https://doi.org/10.1016/j.cmet.2020.06.008
  19. Sci Adv. 2020 Jun;6(26): eaaz9805
    Higuchi-Sanabria R, Shen K, Kelet N, Frankino PA, Durieux J, Bar-Ziv R, Sing CN, Garcia EJ, Homentcovschi S, Sanchez M, Wu R, Tronnes SU, Joe L, Webster B, Ahilon-Jeronimo A, Monshietehadi S, Dallarda S, Pender C, Pon LA, Zoncu R, Dillin A.
      Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPRER. Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1-dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in laat-1 mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.
    DOI:  https://doi.org/10.1126/sciadv.aaz9805
  20. Metab Eng. 2020 Jul 02. pii: S1096-7176(20)30109-9. [Epub ahead of print]
    Zhang S, Wakai S, Sasakura N, Tsutsumi H, Hata Y, Ogino C, Kondo A.
      Pyruvate is a central metabolite for the biological production of various chemicals. In eukaryotes, pyruvate produced by glycolysis is used in conversion to ethanol and lactate and in anabolic metabolism in the cytosol, or is transported into the mitochondria for use as a substrate in the tricarboxylic acid (TCA) cycle. In this study, we focused on controlling pyruvate metabolism in aerobic microorganisms for the biological production of various chemicals. We successfully improved productivity by redirecting pyruvate metabolism in the aerobic filamentous fungus Aspergillus oryzae via the deletion of two genes that encode pyruvate decarboxylase and mitochondrial pyruvate carriers. Production of ethanol as a major byproduct was completely inhibited, and the limited translocation of pyruvate into the mitochondria shifted the metabolism from respiration for energy conversion to the effective production of lactate or 2,3-butandiole, even under aerobic conditions. Metabolomic and transcriptomic analyses showed an emphasis on glycolysis and a repressed TCA cycle. Although the dry mycelial weights of the deletion mutants were reduced compared with those of wild type, the titer and yields of the target products were drastically increased. In particular, the redirection of pyruvate metabolism shifted from anabolism for biomass production to catabolism for the production of target chemicals. Conclusively, our results indicate that the redirection of pyruvate metabolism is a useful strategy in the metabolic engineering of aerobic microorganisms.
    Keywords:  2,3-Butanediol; Aspergillus oryzae; L-lactic acid; Mitochondrial pyruvate carrier; Pyruvate decarboxylase; Pyruvate flux
    DOI:  https://doi.org/10.1016/j.ymben.2020.06.010
  21. J Vis Exp. 2020 Jun 22.
    Traba J, Waldmann TA, Anton OM.
      Natural Killer (NK) cells mediate mainly innate anti-tumor and anti-viral immune responses and respond to a variety of cytokines and other stimuli to promote survival, cellular proliferation, production of cytokines such as interferon gamma (IFNγ) and/or cytotoxicity programs. NK cell activation by cytokine stimulation requires a substantial remodeling of metabolic pathways to support their bioenergetic and biosynthetic requirements. There is a large body of evidence that suggests that impaired NK cell metabolism is associated with a number of chronic diseases including obesity and cancer, which highlights the clinical importance of the availability of a method to determine NK cell metabolism. Here we describe the use of an extracellular flux analyzer, a platform that allows real-time measurements of glycolysis and mitochondrial oxygen consumption, as a tool to monitor changes in the energy metabolism of human NK cells. The method described here also allows for the monitoring of metabolic changes after stimulation of NK cells with cytokines such as IL-15, a system that is currently being investigated in a wide range of clinical trials.
    DOI:  https://doi.org/10.3791/61466
  22. Nat Commun. 2020 Jul 07. 11(1): 3391
    Hanzlikova H, Prokhorova E, Krejcikova K, Cihlarova Z, Kalasova I, Kubovciak J, Sachova J, Hailstone R, Brazina J, Ghosh S, Cirak S, Gleeson JG, Ahel I, Caldecott KW.
      Neurodegeneration is a common hallmark of individuals with hereditary defects in DNA single-strand break repair; a process regulated by poly(ADP-ribose) metabolism. Recently, mutations in the ARH3 (ADPRHL2) hydrolase that removes ADP-ribose from proteins have been associated with neurodegenerative disease. Here, we show that ARH3-mutated patient cells accumulate mono(ADP-ribose) scars on core histones that are a molecular memory of recently repaired DNA single-strand breaks. We demonstrate that the ADP-ribose chromatin scars result in reduced endogenous levels of important chromatin modifications such as H3K9 acetylation, and that ARH3 patient cells exhibit measurable levels of deregulated transcription. Moreover, we show that the mono(ADP-ribose) scars are lost from the chromatin of ARH3-defective cells in the prolonged presence of PARP inhibition, and concomitantly that chromatin acetylation is restored to normal. Collectively, these data indicate that ARH3 can act as an eraser of ADP-ribose chromatin scars at sites of PARP activity during DNA single-strand break repair.
    DOI:  https://doi.org/10.1038/s41467-020-17069-9
  23. Biology (Basel). 2020 Jun 25. pii: E137. [Epub ahead of print]9(6):
    Poznyak AV, Ivanova EA, Sobenin IA, Yet SF, Orekhov AN.
      The role of mitochondria in cardiovascular diseases is receiving ever growing attention. As a central player in the regulation of cellular metabolism and a powerful controller of cellular fate, mitochondria appear to comprise an interesting potential therapeutic target. With the development of DNA sequencing methods, mutations in mitochondrial DNA (mtDNA) became a subject of intensive study, since many directly lead to mitochondrial dysfunction, oxidative stress, deficient energy production and, as a result, cell dysfunction and death. Many mtDNA mutations were found to be associated with chronic human diseases, including cardiovascular disorders. In particular, 17 mtDNA mutations were reported to be associated with ischemic heart disease in humans. In this review, we discuss the involvement of mitochondrial dysfunction in the pathogenesis of atherosclerosis and describe the mtDNA mutations identified so far that are associated with atherosclerosis and its risk factors.
    Keywords:  atherosclerosis; cardiovascular disease; mitochondria; mitochondrial genome
    DOI:  https://doi.org/10.3390/biology9060137
  24. Dev Cell. 2020 Jun 30. pii: S1534-5807(20)30497-4. [Epub ahead of print]
    Li F, Simon MC.
      Solid tumors reside in harsh tumor microenvironments (TMEs) together with various stromal cell types. During tumor progression and metastasis, both tumor and stromal cells undergo rapid metabolic adaptations. Tumor cells metabolically coordinate or compete with their "neighbors" to maintain biosynthetic and bioenergetic demands while escaping immunosurveillance or therapeutic interventions. Here, we provide an update on metabolic communication between tumor cells and heterogeneous stromal components in primary and metastatic TMEs and discuss emerging strategies to target metabolic communications for improved cancer treatments.
    Keywords:  antitumor immunity; combination therapy; immunomodulation; metabolic communication; metabolic symbiosis; metabolism; metastasis; nutrient competition; signaling molecule; stromal cells; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.018
  25. Chembiochem. 2020 Jul 08.
    Maniam S, Maniam S.
      Cancer is the second leading cause of death and, 1 in 6 deaths globally is due to cancer. Cancer metabolism is a complex and one of the most actively researched area in cancer biology. Metabolic reprogramming in cancer cells entails activities which involves several enzymes and metabolites to convert nutrient into building blocks that alter energy metabolism to fuel rapid cell division. Metabolic dependencies in cancer generate signature metabolites that have key regulatory roles in tumorigenesis. In this minireview, we highlight recent advances of the popular methods ingrained in biochemistry research such as stable and flux isotope analysis, and radioisotope labeling which have valuable use in elucidating cancer metabolites. These methods together with analytical tools such as chromatography, nuclear magnetic resonance spectroscopy and mass spectrometry have helped to bring about the exploratory work in understanding the role of important as well as obscure metabolites in cancer cells. Information obtained from these analyses significantly contribute in the diagnosis and prognosis of tumors leading to potential therapeutic targets for cancer therapy.
    Keywords:  Energy metabolism; isotope flux analysis; metabolic reprogramming; radioisotope labeling; stable isotope
    DOI:  https://doi.org/10.1002/cbic.202000290
  26. Bioessays. 2020 Jul 08. e2000083
    Campit SE, Meliki A, Youngson NA, Chandrasekaran S.
      Several metabolites serve as substrates for histone modifications and communicate changes in the metabolic environment to the epigenome. Technologies such as metabolomics and proteomics have allowed us to reconstruct the interactions between metabolic pathways and histones. These technologies have shed light on how nutrient availability can have a dramatic effect on various histone modifications. This metabolism-epigenome cross talk plays a fundamental role in development, immune function, and diseases like cancer. Yet, major challenges remain in understanding the interactions between cellular metabolism and the epigenome. How the levels and fluxes of various metabolites impact epigenetic marks is still unclear. Discussed herein are recent applications and the potential of systems biology methods such as flux tracing and metabolic modeling to address these challenges and to uncover new metabolic-epigenetic interactions. These systems approaches can ultimately help elucidate how nutrients shape the epigenome of microbes and mammalian cells.
    DOI:  https://doi.org/10.1002/bies.202000083
  27. Cancer Cell. 2020 Jun 23. pii: S1535-6108(20)30274-9. [Epub ahead of print]
    Hayes JD, Dinkova-Kostova AT, Tew KD.
      Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP). During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
    Keywords:  AP-1; BACH1; FOXO; HIF-1alpha; HSF1; NADPH generation; NF-κB; NRF2; PGC-1alpha; TP53; adaptation; antioxidant; dormant cancer cell; folate metabolism; glutathione; initiation; metastasis; oxidative stress; pentose phosphate pathway; progression; reactive oxygen species; recurrent disease; redox signaling; reductive glutamine metabolism; thioredoxin; tumorigenesis
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.001
  28. Cell Metab. 2020 Jul 07. pii: S1550-4131(20)30310-7. [Epub ahead of print]32(1): 6-8
    Tesz GJ, Bence KK.
      The abundance of dietary sweeteners and overconsumption of fructose are widely thought to promote metabolic disease. In this issue of Cell Metabolism, Andres-Hernando et al. (2020) identify the liver as the major site of fructose metabolism-mediated metabolic dysfunction and identify a surprising role for intestinal fructose metabolism in driving fructose intake.
    DOI:  https://doi.org/10.1016/j.cmet.2020.06.009
  29. Elife. 2020 Jul 10. pii: e56782. [Epub ahead of print]9
    Lau AN, Li Z, Danai LV, Westermark AM, Darnell AM, Ferreira R, Gocheva V, Sivanand S, Lien EC, Sapp KM, Mayers JR, Biffi G, Chin CR, Davidson SM, Tuveson DA, Jacks T, Matheson NJ, Yilmaz O, Vander Heiden MG.
      Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.
    Keywords:  cancer biology; mouse
    DOI:  https://doi.org/10.7554/eLife.56782
  30. Sci Adv. 2020 Jun;6(26): eaba7509
    Calvo E, Cogliati S, Hernansanz-Agustín P, Loureiro-López M, Guarás A, Casuso RA, García-Marqués F, Acín-Pérez R, Martí-Mateos Y, Silla-Castro JC, Carro-Alvarellos M, Huertas JR, Vázquez J, Enríquez JA.
      Mitochondrial respiratory complexes assemble into supercomplexes (SC). Q-respirasome (III2 + IV) requires the supercomplex assembly factor (SCAF1) protein. The role of this factor in the N-respirasome (I + III2 + IV) and the physiological role of SCs are controversial. Here, we study C57BL/6J mice harboring nonfunctional SCAF1, the full knockout for SCAF1, or the wild-type version of the protein and found that exercise performance is SCAF1 dependent. By combining quantitative data-independent proteomics, 2D Blue native gel electrophoresis, and functional analysis of enriched respirasome fractions, we show that SCAF1 confers structural attachment between III2 and IV within the N-respirasome, increases NADH-dependent respiration, and reduces reactive oxygen species (ROS). Furthermore, the expression of AOX in cells and mice confirms that CI-CIII superassembly segments the CoQ in two pools and modulates CI-NADH oxidative capacity.
    DOI:  https://doi.org/10.1126/sciadv.aba7509
  31. Autophagy. 2020 Jul 05. 1-21
    Sanchez-Garrido J, Shenoy AR.
      Nutrients not only act as building blocks but also as signaling molecules. Nutrient-availability promotes cell growth and proliferation and suppresses catabolic processes, such as macroautophagy/autophagy. These effects are mediated by checkpoint kinases such as MTOR (mechanistic target of rapamycin kinase), which is activated by amino acids and growth factors, and AMP-activated protein kinase (AMPK), which is activated by low levels of glucose or ATP. These kinases have wide-ranging activities that can be co-opted by immune cells upon exposure to danger signals, cytokines or pathogens. Here, we discuss recent insight into the regulation and repurposing of nutrient-sensing responses by the innate immune system during infection. Moreover, we examine how natural mutations and pathogen-mediated interventions can alter the balance between anabolic and autophagic pathways leading to a breakdown in tissue homeostasis and/or host defense.ABBREVIATIONS: AKT1/PKB: AKT serine/threonine kinase 1; ATG: autophagy related; BECN1: beclin 1; CGAS: cyclic GMP-AMP synthase; EIF2AK4/GCN2: eukaryotic translation initiation factor 2 alpha kinase 4; ER: endoplasmic reticulum; FFAR: free fatty acid receptor; GABARAP: GABA type A receptor-associated protein; IFN: interferon; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAPK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; NLR: NOD (nucleotide-binding oligomerization domain) and leucine-rich repeat containing proteins; PI3K, phosphoinositide 3-kinase; PRR: pattern-recognition receptor; PtdIns3K: phosphatidylinositol 3-kinase; RALB: RAS like proto-oncogene B; RHEB: Ras homolog, MTORC1 binding; RIPK1: receptor interacting serine/threonine kinase 1; RRAG: Ras related GTP binding; SQSTM1/p62: sequestosome 1; STING1/TMEM173: stimulator of interferon response cGAMP interactor 1; STK11/LKB1: serine/threonine kinase 11; TBK1: TANK binding kinase 1; TLR: toll like receptor; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6; TRIM: tripartite motif protein; ULK1: unc-51 like autophagy activating kinase 1; V-ATPase: vacuolar-type H+-proton-translocating ATPase.
    Keywords:  AMPK; LC3-associated phagocytosis; MTOR; immunity; microbial pathogenesis; unconventional secretion
    DOI:  https://doi.org/10.1080/15548627.2020.1783119
  32. Cancers (Basel). 2020 Jul 06. pii: E1814. [Epub ahead of print]12(7):
    Shao Y, Franko A, Heni M, Hennenlotter J, Hoene M, Hu C, Liu X, Zhao X, Wang Q, Birkenfeld AL, Todenhöfer T, Stenzl A, Peter A, Häring HU, Lehmann R, Xu G, Lutz SZ.
      Despite it being the most common incident of cancer among men, the pathophysiological mechanisms contributing to prostate cancer (PCa) are still poorly understood. Altered mitochondrial metabolism is postulated to play a role in the development of PCa. To determine the key metabolites (which included mitochondrial oncometabolites), benign prostatic and cancer tissues of patients with PCa were analyzed using capillary electrophoresis and liquid chromatography coupled with mass spectrometry. Gene expression was studied using real-time PCR. In PCa tissues, we found reduced levels of early tricarboxylic acid cycle metabolites, whereas the contents of urea cycle metabolites including aspartate, argininosuccinate, arginine, proline, and the oncometabolite fumarate were higher than that in benign controls. Fumarate content correlated positively with the gene expression of oncogenic HIF1α and NFκB pathways, which were significantly higher in the PCa samples than in the benign controls. Furthermore, data from the TCGA database demonstrated that prostate cancer patients with activated NFκB pathway had a lower survival rate. In summary, our data showed that fumarate content was positively associated with carcinogenic genes.
    Keywords:  NFκB; fumarate; metabolomics; oncometabolite; prostate cancer; urea cycle
    DOI:  https://doi.org/10.3390/cancers12071814
  33. Nature. 2020 Jul 08.
    Ledford H.
      
    Keywords:  Biological techniques; CRISPR-Cas9 genome editing; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-020-02054-5
  34. Annu Rev Nutr. 2020 Jul 06.
    Shu XE, V Swanda R, Qian SB.
      The emergence of genome-wide analyses to interrogate cellular DNA, RNA, and protein content has revolutionized the study of control networks that mediate cellular homeostasis. mRNA translation represents the last step of genetic flow and primarily defines the proteome. Translational regulation is thus critical for gene expression, in particular under nutrient excess or deficiency. Until recently, it was unclear how the global effects of translational control are orchestrated by nutrient signaling pathways. An emerging concept of translational reprogramming addresses how to maintain the expression of specific proteins during nutrient stress by translation of selective mRNAs. In this review, we describe recent advances in our understanding of translational control principles; nutrient-sensing mechanisms; and their dysregulation in human diseases such as diabetes, cancer, and aging. The mechanistic understanding of translational regulation in response to different nutrient conditions may help identify potential dietary and therapeutic targets to improve human health. Please see http://www.annualreviews.org/page/journal/pubdates for expected final online publication date for the Annual Review of Nutrition, Volume 40. 2020.
    DOI:  https://doi.org/10.1146/annurev-nutr-120919-041411
  35. Cancers (Basel). 2020 Jul 02. pii: E1757. [Epub ahead of print]12(7):
    Cuyàs E, Verdura S, Martin-Castillo B, Alarcón T, Lupu R, Bosch-Barrera J, Menendez JA.
      One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system's ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.
    Keywords:  diet; immune checkpoint inhibitors; immune checkpoints; metabolism; nutrition
    DOI:  https://doi.org/10.3390/cancers12071757
  36. EMBO Rep. 2020 Jul 09. e49752
    Fukuda R, Marín-Juez R, El-Sammak H, Beisaw A, Ramadass R, Kuenne C, Guenther S, Konzer A, Bhagwat AM, Graumann J, Stainier DY.
      Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.
    Keywords:  cardiac regeneration; cardiomyocyte proliferation; glycolysis; metabolism; zebrafish
    DOI:  https://doi.org/10.15252/embr.201949752
  37. Front Cell Dev Biol. 2020 ;8 428
    Xu L, Wang X, Tong C.
      Endoplasmic reticulum-mitochondria contact sites (ERMCSs) are dynamic contact regions with a distance of 10-30 nm between the endoplasmic reticulum and mitochondria. Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, including lipid transfer, calcium homeostasis, autophagy, and mitochondrial dynamics. The dysfunction of ERMCS is closely associated with various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In this review, we will summarize the current knowledge of the components and organization of ERMCSs, the methods for monitoring ERMCSs, and the physiological functions of ERMCSs in different model systems. Additionally, we will emphasize the current understanding of the malfunction of ERMCSs and their potential roles in neurodegenerative diseases.
    Keywords:  autophagy; contact sites; endoplasmic reticulum; mitochdonrion; neurodegeneration
    DOI:  https://doi.org/10.3389/fcell.2020.00428
  38. Cell Metab. 2020 Jul 07. pii: S1550-4131(20)30313-2. [Epub ahead of print]32(1): 8-10
    Tung YCL, O'Rahilly S.
      In a recent issue of Cell, Orthofer et al. (2020) present a body of data from mice, flies, and humans that suggest (1) a physiological role for Alk in the normal control of energy balance across several species and (2) a possible contribution of genetic variants in or near ALK to the variability of adiposity in humans, more specifically at its lower end.
    DOI:  https://doi.org/10.1016/j.cmet.2020.06.012
  39. Proc Natl Acad Sci U S A. 2020 Jul 06. pii: 202000238. [Epub ahead of print]
    Weinreb C, Klein AM.
      A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.
    Keywords:  branching processes; clonal barcodes; lineage tracing
    DOI:  https://doi.org/10.1073/pnas.2000238117
  40. Nature. 2020 Jul 08.
    Aushev M, Herbert M.
      
    Keywords:  Biotechnology; Gene therapy
    DOI:  https://doi.org/10.1038/d41586-020-01974-6
  41. Sci Rep. 2020 Jul 06. 10(1): 11060
    Stander Z, Luies L, Mienie LJ, Van Reenen M, Howatson G, Keane KM, Clifford T, Stevenson EJ, Loots DT.
      Endurance athlete performance is greatly dependent on sufficient post-race system recovery, as endurance races have substantial physiological, immunological and metabolic effects on these athletes. To date, the effects of numerous recovery modalities have been investigated, however, very limited literature exists pertaining to metabolic recovery of athletes after endurance races without the utilisation of recovery modalities. As such, this investigation is aimed at identifying the metabolic recovery trend of athletes within 48 h after a marathon. Serum samples of 16 athletes collected 24 h before, immediately after, as well as 24 h and 48 h post-marathon were analysed using an untargeted two-dimensional gas chromatography time-of-flight mass spectrometry metabolomics approach. The metabolic profiles of these comparative time-points indicated a metabolic shift from the overall post-marathon perturbed state back to the pre-marathon metabolic state during the recovery period. Statistical analyses of the data identified 61 significantly altered metabolites including amino acids, fatty acids, tricarboxylic acid cycle, carbohydrates and associated intermediates. These intermediates recovered to pre-marathon related concentrations within 24 h post-marathon, except for xylose which only recovered within 48 h. Furthermore, fluctuations in cholesterol and pyrimidine intermediates indicated the activation of alternative recovery mechanisms. Metabolic recovery of the athletes was attained within 48 h post-marathon, most likely due to reduced need for fuel substrate catabolism. This may result in the activation of glycogenesis, uridine-dependent nucleotide synthesis, protein synthesis, and the inactivation of cellular autophagy. These results may be beneficial in identifying more efficient, targeted recovery approaches to improve athletic performance.
    DOI:  https://doi.org/10.1038/s41598-020-67884-9
  42. Cancer Cell. 2020 Jun 23. pii: S1535-6108(20)30307-X. [Epub ahead of print]
    Wang Z, Sun D, Chen YJ, Xie X, Shi Y, Tabar V, Brennan CW, Bale TA, Jayewickreme CD, Laks DR, Alcantara Llaguno S, Parada LF.
      Glioblastoma, the predominant adult malignant brain tumor, has been computationally classified into molecular subtypes whose functional relevance remains to be comprehensively established. Tumors from genetically engineered glioblastoma mouse models initiated by identical driver mutations in distinct cells of origin portray unique transcriptional profiles reflective of their respective lineage. Here, we identify corresponding transcriptional profiles in human glioblastoma and describe patient-derived xenografts with species-conserved subtype-discriminating functional properties. The oligodendrocyte lineage-associated glioblastoma subtype requires functional ERBB3 and harbors unique therapeutic sensitivities. These results highlight the importance of cell lineage in glioblastoma independent of driver mutations and provide a methodology for functional glioblastoma classification for future clinical investigations.
    Keywords:  Erbb3; GBM; PDX; cell of origin; glioblastoma; molecular classification; molecular subtype; mouse model; neural stem cell; oligodendrocyte lineage cell
    DOI:  https://doi.org/10.1016/j.ccell.2020.06.003
  43. J Biol Chem. 2020 Jul 06. pii: jbc.RA120.013960. [Epub ahead of print]
    Li Y, Lou W, Grevel A, Böttinger L, Liang Z, Ji J, Patil VA, Liu J, Ye C, Hüttemann M, Becker T, Greenberg ML.
      Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin-deficiency on iron homeostasis in the mouse myoblast model of BTHS, TAZ-KO (tafazzin knockout) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron-sulfur cluster (Fe-S) enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective Fe-S biogenesis. We observed decreased levels of Yfh1/frataxin, an essential component of the Fe-S biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in Fe-S biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.
    Keywords:  Barth syndrome; cardiolipin; frataxin; iron; mitochondria; protein import
    DOI:  https://doi.org/10.1074/jbc.RA120.013960
  44. iScience. 2020 Jun 26. pii: S2589-0042(20)30433-8. [Epub ahead of print]23(6): 101247
    Kwon SM, Lee YK, Min S, Woo HG, Wang HJ, Yoon G.
      Mitochondrial ribosomes (mitoribosomes), the specialized translational machinery for mitochondrial genes, exclusively encode the subunits of the oxidative phosphorylation (OXPHOS) system. Although OXPHOS dysfunctions are associated with hepatic disorders including hepatocellular carcinoma (HCC), their underlying mechanisms remain poorly elucidated. In this study, we aimed to investigate the effects of mitoribosome defects on OXPHOS and HCC progression. By generating a gene signature from HCC transcriptome data, we developed a scoring system, i.e., mitoribosome defect score (MDS), which represents the degree of mitoribosomal defects in cancers. The MDS showed close associations with the clinical outcomes of patients with HCC and with gene functions such as oxidative phosphorylation, cell-cycle activation, and epithelial-mesenchymal transition. By analyzing immune profiles, we observed that mitoribosomal defects are also associated with immunosuppression and evasion. Taken together, our results provide new insights into the roles of mitoribosome defects in HCC progression.
    Keywords:  Cancer; Cancer Systems Biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2020.101247
  45. Cell Rep. 2020 Jul 07. pii: S2211-1247(20)30860-3. [Epub ahead of print]32(1): 107879
    Zhang S, Wang C, Ma B, Xu M, Xu S, Liu J, Tian Y, Fu Y, Luo Y.
      Mutant p53 (mutp53) loses its tumor suppressor properties but gains oncogenic functions of driving malignancy. However, it remains largely unknown how mutp53 drives cancer metastasis. Here, we show that wild-type p53 (WTp53) suppresses the secretion of heat shock protein 90-alpha (Hsp90α), whereas mutp53 enhances Hsp90α vesicular trafficking and exosome-mediated secretion. Long-term delivery of an antibody that blocks extracellular Hsp90α (eHsp90α) function extends the survival of p53-/- mice and attenuates the invasiveness of p53 mutant tumors. Furthermore, mass spectrometry and functional analysis identified a critical role for Rab coupling protein (RCP) in mutp53-induced Hsp90α secretion. RCP knockdown decreases eHsp90α levels and inhibits malignant progression. Notably, recombinant Hsp90α re-introduction markedly rescues the impaired migration and invasion abilities caused by RCP depletion. Taken together, these findings elucidate the molecular mechanisms by which mutp53 executes oncogenic activities via its downstream RCP-mediated Hsp90α secretion and a strategy to treat human cancers expressing mutp53 proteins.
    Keywords:  Rab coupling protein; cancer metastasis; extracellular Hsp90α; mutant p53; vesicular trafficking
    DOI:  https://doi.org/10.1016/j.celrep.2020.107879
  46. Trends Endocrinol Metab. 2020 Jul 01. pii: S1043-2760(20)30121-1. [Epub ahead of print]
    Dumas SJ, García-Caballero M, Carmeliet P.
      Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting of endothelial cells (ECs) through growth factor inhibition is limited by insufficient efficacy and resistance, a new paradigm for modulating angiogenesis by targeting EC metabolism has emerged. Findings from the past decade highlight how ECs adapt their metabolism to proliferate or migrate during vessel sprouting, or to maintain the vascular barrier and protect themselves against oxidative stress in the high-oxygen environment they are exposed to in healthy conditions. We overview key endothelial metabolic pathways underlying the different EC phenotypes, as well as potential opportunities for targeting EC metabolism in therapeutic settings.
    Keywords:  angiogenesis; endothelial cell; metabolism; phalanx/tip/stalk cell; therapeutic target
    DOI:  https://doi.org/10.1016/j.tem.2020.05.009
  47. Cell. 2020 Jul 09. pii: S0092-8674(20)30744-3. [Epub ahead of print]182(1): 200-225.e35
    Gillette MA, Satpathy S, Cao S, Dhanasekaran SM, Vasaikar SV, Krug K, Petralia F, Li Y, Liang WW, Reva B, Krek A, Ji J, Song X, Liu W, Hong R, Yao L, Blumenberg L, Savage SR, Wendl MC, Wen B, Li K, Tang LC, MacMullan MA, Avanessian SC, Kane MH, Newton CJ, Cornwell M, Kothadia RB, Ma W, Yoo S, Mannan R, Vats P, Kumar-Sinha C, Kawaler EA, Omelchenko T, Colaprico A, Geffen Y, Maruvka YE, da Veiga Leprevost F, Wiznerowicz M, Gümüş ZH, Veluswamy RR, Hostetter G, Heiman DI, Wyczalkowski MA, Hiltke T, Mesri M, Kinsinger CR, Boja ES, Omenn GS, Chinnaiyan AM, Rodriguez H, Li QK, Jewell SD, Thiagarajan M, Getz G, Zhang B, Fenyö D, Ruggles KV, Cieslik MP, Robles AI, Clauser KR, Govindan R, Wang P, Nesvizhskii AI, Ding L, Mani DR, Carr SA, .
      To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
    Keywords:  CPTAC; acetylation; adenocarcinoma; genomics; lung cancer; mass spectrometry; phosphorylation; protein; proteogenomics; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2020.06.013
  48. Nature. 2020 Jul 08.
    Magistretti PJ.
      
    Keywords:  Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-020-01975-5
  49. Antioxid Redox Signal. 2020 Jul 07.
    Conway ME.
      Significance Unique to the branched-chain aminotransferase (BCAT) proteins is their redox active CXXC motif. Subject to post translational modification by reactive oxygen and nitrogen species, these proteins have the potential to adopt numerous cellular roles, which may be fundamental to their role in oncogenesis and neurodegenerative diseases. An understanding of the interplay of the redox regulation of BCAT with important cell signalling mechanisms will identify new targets for future therapeutics. Recent advances The BCAT proteins have been assigned novel thiol oxidoreductase activity that can accelerate the refolding of proteins, in particular when S-glutathionylated, supporting a chaperone role for BCAT in protein folding. Other metabolic proteins were also shown to have peroxide-mediated redox associations with BCAT, indicating that the cellular function of BCAT is more diverse. Critical Issues Whilst the role of branched-chain amino acid metabolism and its metabolites have dominated aspects of cancer research, less is known about the role of BCAT. The importance of the CXXC motif in regulating BCAT activity under hypoxic conditions, a characteristic of tumours, has not been addressed. Understanding how these proteins operate under various cellular redox conditions will become important, in particular with respect to their moonlighting roles. Future Directions Advances in the quantification of thiols, their measurement and the manipulation of metabolons that rely on redox-based interactions should accelerate the investigation of the cellular role of moonlighting proteins such as BCAT. Given the importance of crosstalk between signalling pathways, research should focus more on these 'housekeeping' proteins paying attention to their wider application.
    DOI:  https://doi.org/10.1089/ars.2020.8118
  50. Nat Commun. 2020 Jul 08. 11(1): 3412
    Bibby JA, Purvis HA, Hayday T, Chandra A, Okkenhaug K, Rosenzweig S, Aksentijevich I, Wood M, Lachmann HJ, Kemper C, Cope AP, Perucha E.
      Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.
    DOI:  https://doi.org/10.1038/s41467-020-17179-4
  51. Cell Rep. 2020 Jul 07. pii: S2211-1247(20)30829-9. [Epub ahead of print]32(1): 107848
    Guerra L, Bonetti L, Brenner D.
      Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations.
    DOI:  https://doi.org/10.1016/j.celrep.2020.107848
  52. Cell Rep. 2020 Jul 07. pii: S2211-1247(20)30828-7. [Epub ahead of print]32(1): 107847
    Santiago L, Castro M, Sanz-Pamplona R, Garzón M, Ramirez-Labrada A, Tapia E, Moreno V, Layunta E, Gil-Gómez G, Garrido M, Peña R, Lanuza PM, Comas L, Jaime-Sanchez P, Uranga-Murillo I, Del Campo R, Pelegrín P, Camerer E, Martínez-Lostao L, Muñoz G, Uranga JA, Alcalde A, Galvez EM, Ferrandez A, Bird PI, Metkar S, Arias MA, Pardo J.
      If not properly regulated, the inflammatory immune response can promote carcinogenesis, as evident in colorectal cancer (CRC). Aiming to gain mechanistic insight into the link between inflammation and CRC, we perform transcriptomics analysis of human CRC, identifying a strong correlation between expression of the serine protease granzyme A (GzmA) and inflammation. In a dextran sodium sulfate and azoxymethane (DSS/AOM) mouse model, deficiency and pharmacological inhibition of extracellular GzmA both attenuate gut inflammation and prevent CRC development, including the initial steps of cell transformation and epithelial-to-mesenchymal transition. Mechanistically, extracellular GzmA induces NF-κB-dependent IL-6 production in macrophages, which in turn promotes STAT3 activation in cultured CRC cells. Accordingly, colon tissues from DSS/AOM-treated, GzmA-deficient animals present reduced levels of pSTAT3. By identifying GzmA as a proinflammatory protease that promotes CRC development, these findings provide information on mechanisms that link immune cell infiltration to cancer progression and present GzmA as a therapeutic target for CRC.
    Keywords:  IL6; STAT3; colorectal cancer; extracellular; granzyme; gut; inflammation; macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2020.107847
  53. Immunity. 2020 Jul 01. pii: S1074-7613(20)30271-5. [Epub ahead of print]
    Kumagai S, Togashi Y, Sakai C, Kawazoe A, Kawazu M, Ueno T, Sato E, Kuwata T, Kinoshita T, Yamamoto M, Nomura S, Tsukamoto T, Mano H, Shitara K, Nishikawa H.
      Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.
    Keywords:  PI3K inhibitor; RHOA mutation; fatty acid metabolism; gastric cancer; non-inflamed tumor; regulatory T cell
    DOI:  https://doi.org/10.1016/j.immuni.2020.06.016