bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021‒01‒10
37 papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Nat Metab. 2021 Jan 04.
    Sang L, Ju HQ, Yang Z, Ge Q, Zhang Z, Liu F, Yang L, Gong H, Shi C, Qu L, Chen H, Wu M, Chen H, Li R, Zhuang Q, Piao H, Yan Q, Yu W, Wang L, Shao J, Liu J, Wang W, Zhou T, Lin A.
      Organelles use specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution and function of molecules such as long non-coding RNAs (lncRNAs) in cellular homeostasis and diseases has not been fully achieved. Here, we reveal the diverse and abundant subcellular distribution of organelle-associated lncRNAs from mitochondria, lysosomes and endoplasmic reticulum. Among them, we identify the mitochondrially localized lncRNA growth-arrest-specific 5 (GAS5) as a tumour suppressor in maintaining cellular energy homeostasis. Mechanistically, energy-stress-induced GAS5 modulates mitochondrial tricarboxylic acid flux by disrupting metabolic enzyme tandem association of fumarate hydratase, malate dehydrogenase and citrate synthase, the canonical members of the tricarboxylic acid cycle. GAS5 negatively correlates with levels of its associated mitochondrial metabolic enzymes in tumours and benefits overall survival in individuals with breast cancer. Together, our detailed annotation of subcellular lncRNA distribution identifies a functional role for lncRNAs in regulating cellular metabolic homeostasis, highlighting organelle-associated lncRNAs as potential clinical targets to manipulate cellular metabolism and diseases.
    DOI:  https://doi.org/10.1038/s42255-020-00325-z
  2. Front Cell Dev Biol. 2020 ;8 603688
    Jiang C, Moorthy BT, Patel DM, Kumar A, Morgan WM, Alfonso B, Huang J, Lampidis TJ, Isom DG, Barrientos A, Fontanesi F, Zhang F.
      Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the regulation of metabolism and apoptosis. Although mitochondria play relevant roles in these processes in health and disease, a causal relationship between ATE1 activity and mitochondrial biology has yet to be established. Here, we report a phylogenetic analysis that traces the roots of ATE1 to alpha-proteobacteria, the mitochondrion microbial ancestor. We then demonstrate that a small fraction of ATE1 localizes within mitochondria. Furthermore, the absence of ATE1 influences the levels, organization, and function of respiratory chain complexes in mouse cells. Specifically, ATE1-KO mouse embryonic fibroblasts have increased levels of respiratory supercomplexes I+III2+IVn. However, they have decreased mitochondrial respiration owing to severely lowered complex II levels, which leads to accumulation of succinate and downstream metabolic effects. Taken together, our findings establish a novel pathway for mitochondrial function regulation that might explain ATE1-dependent effects in various disease conditions, including cancer and aging, in which metabolic shifts are part of the pathogenic or deleterious underlying mechanism.
    Keywords:  arginylation; arginyltransferase; biogenesis; mitochondria; respiration; respiratory chain complexes
    DOI:  https://doi.org/10.3389/fcell.2020.603688
  3. Cell Metab. 2020 Dec 24. pii: S1550-4131(20)30661-6. [Epub ahead of print]
    Levoux J, Prola A, Lafuste P, Gervais M, Chevallier N, Koumaiha Z, Kefi K, Braud L, Schmitt A, Yacia A, Schirmann A, Hersant B, Sid-Ahmed M, Ben Larbi S, Komrskova K, Rohlena J, Relaix F, Neuzil J, Rodriguez AM.
      Platelets are known to enhance the wound-healing activity of mesenchymal stem cells (MSCs). However, the mechanism by which platelets improve the therapeutic potential of MSCs has not been elucidated. Here, we provide evidence that, upon their activation, platelets transfer respiratory-competent mitochondria to MSCs primarily via dynamin-dependent clathrin-mediated endocytosis. We found that this process enhances the therapeutic efficacy of MSCs following their engraftment in several mouse models of tissue injury, including full-thickness cutaneous wound and dystrophic skeletal muscle. By combining in vitro and in vivo experiments, we demonstrate that platelet-derived mitochondria promote the pro-angiogenic activity of MSCs via their metabolic remodeling. Notably, we show that activation of the de novo fatty acid synthesis pathway is required for increased secretion of pro-angiogenic factors by platelet-preconditioned MSCs. These results reveal a new mechanism by which platelets potentiate MSC properties and underline the importance of testing platelet mitochondria quality prior to their clinical use.
    Keywords:  angiogenesis; cell therapy; citrate; de novo; fatty acid synthesis; intercellular mitochondria transfer; mesenchymal stem cells; metabolism reprogramming; mitochondria; mitochondrial respiration; platelets
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.006
  4. Circ Res. 2021 Jan 06.
    Oeing CU, Jun S, Mishra S, Dunkerly-Eyring B, Chen A, Grajeda MI, Tahir U, Gerszten RE, Paolocci N, Ranek MJ, Kass DA.
      Rationale: The mechanistic target of rapamycin complex-1 (mTORC1) controls metabolism and protein homeostasis, and is activated following ischemic reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little studied. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied prior to ischemic stress. This can be circumvented by regulating one serine (S1365) on tuberous sclerosis complex (TSC2) to achieve bi-directional mTORC1 modulation but only with TCS2-regulated co-stimulation. Objective: We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and IPC by amplifying mTORC1 activity to favor glycolytic metabolism. Methods and Results: Mice with either S1365A (TSC2SA; phospho-null) or S1365E (TSC2SE; phosphomimetic) knock-in mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2SA mice had amplified mTORC1 activation and improved heart function compared to WT and TSC2SE hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2SE hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2SA, with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acyl-carnitine levels declined during ischemia. The relative IR protection in TSC2SA was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in WT and TSC2SE but not TSC2SA which had the worst post-IR function under these conditions. Conclusions: TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC.
    Keywords:  mechanistic target of rapamycin; tuberous sclerosis complex
    DOI:  https://doi.org/10.1161/CIRCRESAHA.120.317710
  5. Cell Metab. 2021 Jan 05. pii: S1550-4131(20)30663-X. [Epub ahead of print]33(1): 128-144.e9
    Huang N, Li F, Zhang M, Zhou H, Chen Z, Ma X, Yang L, Wu X, Zhong J, Xiao F, Yang X, Zhao K, Li X, Xia X, Liu Z, Gao S, Zhang N.
      The metabolic role of micropeptides generated from untranslated regions remains unclear. Here we describe MP31, a micropeptide encoded by the upstream open reading frame (uORF) of phosphatase and tensin homolog (PTEN) acting as a "circuit breaker" that limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+). Knocking out the MP31 homolog in mice enhanced global lactate metabolism, manifesting as accelerated oxidative phosphorylation (OXPHOS) and increased lactate consumption and production. Conditional knockout (cKO) of MP31 homolog in mouse astrocytes initiated gliomagenesis and shortened the overall survival of the animals, establishing a tumor-suppressing role for MP31. Recombinant MP31 administered intraperitoneally penetrated the blood-brain barrier and inhibited mice GBM xenografts without neurological toxicity, suggesting the clinical implication and application of this micropeptide. Our findings reveal a novel mode of MP31-orchestrated lactate metabolism reprogramming in glioblastoma.
    Keywords:  LDH; MP31; OXPHOS; PTEN; glioblastoma; lactate oxidation; tumorigenesis; uORF
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.008
  6. Nat Metab. 2021 Jan 04.
    Elia I, Haigis MC.
      Metabolic transformation is a hallmark of cancer and a critical target for cancer therapy. Cancer metabolism and behaviour are regulated by cell-intrinsic factors as well as metabolite availability in the tumour microenvironment (TME). This metabolic niche within the TME is shaped by four tiers of regulation: (1) intrinsic tumour cell metabolism, (2) interactions between cancer cells and non-cancerous cells, (3) tumour location and heterogeneity and (4) whole-body metabolic homeostasis. Here, we define these modes of metabolic regulation and review how distinct cell types contribute to the metabolite composition of the TME. Finally, we connect these insights to understand how each of these tiers offers unique therapeutic potential to modulate the metabolic profile and function of all cells inhabiting the TME.
    DOI:  https://doi.org/10.1038/s42255-020-00317-z
  7. Biochim Biophys Acta Bioenerg. 2021 Jan 04. pii: S0005-2728(20)30217-6. [Epub ahead of print] 148367
    Chang JC, Go S, Gilglioni EH, Duijst S, Panneman DM, Rodenburg RJ, Li HL, Huang HL, Levin LR, Buck J, Verhoeven AJ, Oude Elferink RPJ.
      The evolutionarily conserved soluble adenylyl cyclase (sAC, ADCY10) mediates cAMP signaling exclusively in intracellular compartments. Because sAC activity is sensitive to local concentrations of ATP, bicarbonate, and free Ca2+, sAC is potentially an important metabolic sensor. Nonetheless, little is known about how sAC regulates energy metabolism in intact cells. In this study, we demonstrated that both pharmacological and genetic suppression of sAC resulted in increased lactate secretion and decreased pyruvate secretion in multiple cell lines and primary cultures of mouse hepatocytes and cholangiocytes. The increased extracellular lactate-to-pyruvate ratio upon sAC suppression reflected an increased cytosolic free [NADH]/[NAD+] ratio, which was corroborated by using the NADH/NAD+ redox biosensor Peredox-mCherry. Mechanistic studies in permeabilized HepG2 cells showed that sAC inhibition specifically suppressed complex I of the mitochondrial respiratory chain. A survey of cAMP effectors revealed that only selective inhibition of exchange protein activated by cAMP 1 (Epac1), but not protein kinase A (PKA) or Epac2, suppressed complex I-dependent respiration and significantly increased the cytosolic NADH/NAD+ redox state. Analysis of the ATP production rate and the adenylate energy charge showed that inhibiting sAC reciprocally affects ATP production by glycolysis and oxidative phosphorylation while maintaining cellular energy homeostasis. In conclusion, our study shows that, via the regulation of complex I-dependent mitochondrial respiration, sAC-Epac1 signaling regulates the cytosolic NADH/NAD+ redox state, and coordinates oxidative phosphorylation and glycolysis to maintain cellular energy homeostasis. As such, sAC is effectively a bioenergetic switch between aerobic glycolysis and oxidative phosphorylation at the post-translational level.
    Keywords:  Exchange protein directly activated by cAMP (Epac); Glycolysis; NADH/NAD(+) redox state; Oxidative phosphorylation; Protein kinase a; Soluble adenylyl cyclase
    DOI:  https://doi.org/10.1016/j.bbabio.2020.148367
  8. Cell Metab. 2021 Jan 05. pii: S1550-4131(20)30664-1. [Epub ahead of print]33(1): 9-20
    Pathria G, Ronai ZA.
      Sustained proliferative potential of cancer cells creates heightened energetic and biosynthetic demands. The resulting overt dependence of cancer cells on unperturbed nutrient supply has prompted a widespread interest in amino acid restriction strategies as potential cancer therapeutics. However, owing to rapid signaling and metabolic reprogramming in cancer cells, the prospects for success of amino acid restriction approaches remain unclear. We thus recognize that the identification of co-vulnerabilities of amino acid-restricted cancers may inform actionable targets for effective combined interventions. In this perspective, we outline the current state of key cellular mechanisms underlying adaptation to amino acid restriction and discuss the role of signal transduction pathways governing cancer cell resistance to amino acid restriction, with potential ramifications for the design of future therapeutic efforts.
    Keywords:  ATF4; MAPK; NRF2; adaptation; amino acids; c-MYC; cancer; mTORC1; metabolism; resistance
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.009
  9. Nat Genet. 2021 Jan;53(1): 86-99
    Woo XY, Giordano J, Srivastava A, Zhao ZM, Lloyd MW, de Bruijn R, Suh YS, Patidar R, Chen L, Scherer S, Bailey MH, Yang CH, Cortes-Sanchez E, Xi Y, Wang J, Wickramasinghe J, Kossenkov AV, Rebecca VW, Sun H, Mashl RJ, Davies SR, Jeon R, Frech C, Randjelovic J, Rosains J, Galimi F, Bertotti A, Lafferty A, O'Farrell AC, Modave E, Lambrechts D, Ter Brugge P, Serra V, Marangoni E, El Botty R, Kim H, Kim JI, Yang HK, Lee C, Dean DA, Davis-Dusenbery B, Evrard YA, Doroshow JH, Welm AL, Welm BE, Lewis MT, Fang B, Roth JA, Meric-Bernstam F, Herlyn M, Davies MA, Ding L, Li S, Govindan R, Isella C, Moscow JA, Trusolino L, Byrne AT, Jonkers J, Bult CJ, Medico E, Chuang JH, , .
      Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.
    DOI:  https://doi.org/10.1038/s41588-020-00750-6
  10. Nat Commun. 2021 01 04. 12(1): 102
    Wang Y, Tang B, Long L, Luo P, Xiang W, Li X, Wang H, Jiang Q, Tan X, Luo S, Li H, Wang Z, Chen Z, Leng Y, Jiang Z, Wang Y, Ma L, Wang R, Zeng C, Liu Z, Wang Y, Miao H, Shi C.
      Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.
    DOI:  https://doi.org/10.1038/s41467-020-20315-9
  11. Metabolites. 2021 Jan 02. pii: E28. [Epub ahead of print]11(1):
    Ohshima K, Morii E.
      Cancer cells face various metabolic challenges during tumor progression, including growth in the nutrient-altered and oxygen-deficient microenvironment of the primary site, intravasation into vessels where anchorage-independent growth is required, and colonization of distant organs where the environment is distinct from that of the primary site. Thus, cancer cells must reprogram their metabolic state in every step of cancer progression. Metabolic reprogramming is now recognized as a hallmark of cancer cells and supports cancer growth. Elucidating the underlying mechanisms of metabolic reprogramming in cancer cells may help identifying cancer targets and treatment strategies. This review summarizes our current understanding of metabolic reprogramming during cancer progression and metastasis, including cancer cell adaptation to the tumor microenvironment, defense against oxidative stress during anchorage-independent growth in vessels, and metabolic reprogramming during metastasis.
    Keywords:  anchorage-independent growth; cancer metabolism; cancer metastasis; metabolic reprograming; therapeutic strategy; tumor microenvironments
    DOI:  https://doi.org/10.3390/metabo11010028
  12. Front Oncol. 2020 ;10 570656
    Sang L, He YJ, Kang J, Ye H, Bai W, Luo XD, Sun J.
      Overexpression of DGUOK promotes mitochondria oxidative phosphorylation and lung adenocarcinoma progression. However, the role and mechanism of DGUOK in regulation of mitochondria function and lung cancer progression still poorly understood. Here we demonstrated that DGUOK regulated NAD+ biogenesis. Depletion of the DGUOK significantly decreased NAD+ level. Furthermore, knockout of the DGUOK considerably reduced expression of the NMNAT2, a key molecule controlling NAD+ synthesis, at both mRNA and protein levels. Ectopic expression of the NMNAT2 abrogated the effect of knockdown of DGUOK on NAD+. Notably, this regulation is independent of DGUOK -mediated mitochondria complex I activity. We also showed that NMNAT2 was highly expressed in lung adenocarcinoma and negatively correlated with the patient overall survival. Our study suggested that DGUOK regulates NAD+ in a NMNAT2 dependent manner and DGUOK-NMNAT2-NAD+ axis could be a potential therapeutic target in lung adenocarcinoma.
    Keywords:  NAD+; NMNAT2; deoxyguanosine kinase; lung adenocarcinoma; mitochondria complex I
    DOI:  https://doi.org/10.3389/fonc.2020.570656
  13. Nat Cell Biol. 2021 Jan;23(1): 75-86
    Wu J, Li G, Li L, Li D, Dong Z, Jiang P.
      Nutrient availability is central for T-cell functions and immune responses. Here we report that CD8+ T-cell activation and anti-tumour responses are strongly potentiated by the non-essential amino acid Asn. Increased Asn levels enhance CD8+ T-cell activation and effector functions against tumour cells in vitro and in vivo. Conversely, restriction of dietary Asn, ASNase administration or inhibition of the Asn transporter SLC1A5 impairs the activity and responses of CD8+ T cells. Mechanistically, Asn does not directly alter cellular metabolic fluxes; it instead binds the SRC-family protein tyrosine kinase LCK and orchestrates LCK phosphorylation at Tyr 394 and 505, thereby leading to enhanced LCK activity and T-cell-receptor signalling. Thus, our findings reveal a critical and metabolism-independent role for Asn in the direct modulation of the adaptive immune response by controlling T-cell activation and efficacy, and further uncover that LCK is a natural Asn sensor signalling Asn sufficiency to T-cell functions.
    DOI:  https://doi.org/10.1038/s41556-020-00615-4
  14. Cell Metab. 2021 Jan 05. pii: S1550-4131(20)30670-7. [Epub ahead of print]33(1): 33-50
    Xu D, Shao F, Bian X, Meng Y, Liang T, Lu Z.
      Key pathological, including oncogenic, signaling pathways regulate the canonical functions of metabolic enzymes that serve the cellular metabolic needs. Importantly, these signaling pathways also confer a large number of metabolic enzymes to have noncanonical or nonmetabolic functions that are referred to as "moonlighting" functions. In this review, we highlight how aberrantly regulated metabolic enzymes with such activities play critical roles in the governing of a wide spectrum of instrumental cellular activities, including gene expression, cell-cycle progression, DNA repair, cell proliferation, survival, apoptosis, and tumor microenvironment remodeling, thereby promoting the pathologic progression of disease, including cancer.
    Keywords:  DNA repair; apoptosis; cell proliferation; cell-cycle progression; gene expression; metabolic enzyme; noncanonical function; survival; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.015
  15. Front Oncol. 2020 ;10 604143
    Barbato A, Scandura G, Puglisi F, Cambria D, La Spina E, Palumbo GA, Lazzarino G, Tibullo D, Di Raimondo F, Giallongo C, Romano A.
      The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.
    Keywords:  OX-PHOS; acute myeloid leukemia; chronic lymphatic leukemia; lymphoma; mitochondria; multiple myeloma
    DOI:  https://doi.org/10.3389/fonc.2020.604143
  16. Cell Death Differ. 2021 Jan 04.
    Ottens F, Franz A, Hoppe T.
      Perturbation of metabolism elicits cellular stress which profoundly modulates the cellular proteome and thus protein homeostasis (proteostasis). Consequently, changes in the cellular proteome due to metabolic shift require adaptive mechanisms by molecular protein quality control. The mechanisms vitally controlling proteostasis embrace the entire life cycle of a protein involving translational control at the ribosome, chaperone-assisted native folding, and subcellular sorting as well as proteolysis by the proteasome or autophagy. While metabolic imbalance and proteostasis decline have been recognized as hallmarks of aging and age-associated diseases, both processes are largely considered independently. Here, we delineate how proteome stability is governed by insulin/IGF1 signaling (IIS), mechanistic target of Rapamycin (TOR), 5' adenosine monophosphate-activated protein kinase (AMPK), and NAD-dependent deacetylases (Sir2-like proteins known as sirtuins). This comprehensive overview is emphasizing the regulatory interconnection between central metabolic pathways and proteostasis, indicating the relevance of shared signaling nodes as targets for future therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41418-020-00682-y
  17. Redox Biol. 2020 Dec 24. pii: S2213-2317(20)31051-X. [Epub ahead of print] 101846
    Szabo I, Zoratti M, Biasutto L.
      Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.
    Keywords:  Cancer; Channel interactions; Drug targeting; Ion channels; Mitochondria
    DOI:  https://doi.org/10.1016/j.redox.2020.101846
  18. Cell Rep. 2021 Jan 05. pii: S2211-1247(20)31568-0. [Epub ahead of print]34(1): 108579
    Murakami K, Kurotaki D, Kawase W, Soma S, Fukuchi Y, Kunimoto H, Yoshimi R, Koide S, Oshima M, Hishiki T, Hayakawa N, Matsuura T, Oda M, Yanagisawa K, Kobayashi H, Haraguchi M, Atobe Y, Funakoshi K, Iwama A, Takubo K, Okamoto S, Tamura T, Nakajima H.
      O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.
    Keywords:  O-GlcNAcylation; O-linked N-acetylglucosamine transferase; OGT; PINK1; hematopoietic progenitor cell; hematopoietic stem cell; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2020.108579
  19. J Clin Invest. 2021 Jan 04. pii: 133081. [Epub ahead of print]131(1):
    Amoedo ND, Sarlak S, Obre E, Esteves P, Bégueret H, Kieffer Y, Rousseau B, Dupis A, Izotte J, Bellance N, Dard L, Redonnet-Vernhet I, Punzi G, Rodrigues MF, Dumon E, Mafhouf W, Guyonnet-Dupérat V, Gales L, Palama T, Bellvert F, Dugot-Senan N, Claverol S, Baste JM, Lacombe D, Rezvani HR, Pierri CL, Mechta-Grigoriou F, Thumerel M, Rossignol R.
      Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.
    Keywords:  Bioenergetics; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI133081
  20. Physiol Rep. 2021 Jan;9(1): e14684
    Patel MS, Mahmood S, Jung J, Rideout TC.
      The Pyruvate Dehydrogenase Complex (PDC), a key enzyme in glucose metabolism, catalyzes an irreversible oxidative decarboxylation reaction of pyruvate to acetyl-CoA, linking the cytosolic glycolytic pathway to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Earlier we reported a down-regulation of several key hepatic lipogenic enzymes and their upstream regulators in liver-specific PDC-deficient mouse (L-PDCKO model by deleting the Pdha1 gene). In this study we investigated gene expression profiles of key glycolytic enzymes and other proteins that respond to various metabolic stresses in liver from L-PDCKO mice. Transcripts of several, such as hexokinase 2, phosphoglycerate kinase 1, pyruvate kinase muscle-type 2, and lactate dehydrogenase B as well as those for the nonglycolysis-related proteins, CD-36, C/EBP homologous protein, and peroxisome proliferator-activated receptor γ, were up-regulated in L-PDCKO liver whereas hypoxia-induced factor-1α, pyruvate dehydrogenase kinase 1 and Sirtuin 1 transcripts were down-regulated. The protein levels of pyruvate kinase muscle-type 2 and lactate dehydrogenase B were increased whereas that of lactate dehydrogenase A was decreased in PDC-deficient mouse liver. Analysis of endoplasmic reticulum and oxidative stress indicators suggests that the L-PDCKO liver showed evidence of the former but not the latter. These findings indicate that (i) liver-specific PDC deficiency is sufficient to induce "aerobic glycolysis characteristic" in mouse liver, and (ii) the mechanism(s) responsible for these changes appears distinct from that which induces the Warburg effect in some cancer cells.
    Keywords:  Liver PDC deficiency; PKM2 and LDHB gene expression; SIRT1 down-regulation; aerobic glycolysis
    DOI:  https://doi.org/10.14814/phy2.14684
  21. Cancer Res. 2021 Jan 07. pii: canres.1847.2020. [Epub ahead of print]
    Miller KD, Pniewski K, Perry CE, Papp SB, Shaffer JD, Velasco-Silva JN, Casciano JC, Aramburu TM, Srikanth YVV, Cassel J, Skordalakes E, Kossenkov AV, Salvino JM, Schug ZT.
      Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small molecule inhibitor that acts as a transition state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacological inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1847
  22. Nat Genet. 2021 Jan;53(1): 16-26
    Najumudeen AK, Ceteci F, Fey SK, Hamm G, Steven RT, Hall H, Nikula CJ, Dexter A, Murta T, Race AM, Sumpton D, Vlahov N, Gay DM, Knight JRP, Jackstadt R, Leach JDG, Ridgway RA, Johnson ER, Nixon C, Hedley A, Gilroy K, Clark W, Malla SB, Dunne PD, Rodriguez-Blanco G, Critchlow SE, Mrowinska A, Malviya G, Solovyev D, Brown G, Lewis DY, Mackay GM, Strathdee D, Tardito S, Gottlieb E, , Takats Z, Barry ST, Goodwin RJA, Bunch J, Bushell M, Campbell AD, Sansom OJ.
      Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
    DOI:  https://doi.org/10.1038/s41588-020-00753-3
  23. Autophagy. 2021 Jan 08.
    Lim Y, Berry B, Viteri S, McCall M, Park EC, Rongo C, Brookes PS, Nehrke K.
      Mitochondrial quality control (MQC) balances organelle adaptation and elimination, and mechanistic crosstalk between the underlying molecular processes affects subsequent stress outcomes. FUNDC1 (FUN14 domain containing 1) is a mammalian mitophagy receptor that responds to hypoxia-reoxygenation (HR) stress. Here, we provide evidence that FNDC-1 is the C. elegans ortholog of FUNDC1, and that its loss protects against injury in a worm model of HR. This protection depends upon ATFS-1, a transcription factor that is central to the mitochondrial unfolded protein response (UPRmt). Global mRNA and metabolite profiling suggest that atfs-1-dependent stress responses and metabolic remodeling occur in response to the loss of fndc-1. These data support a role for FNDC-1 in non-hypoxic MQC, and further suggest that these changes are prophylactic in relation to subsequent HR. Our results highlight functional coordination between mitochondrial adaptation and elimination that organizes stress responses and metabolic rewiring to protect against HR injury.
    Keywords:   C. elegans ; hypoxia-reoxygenation (HR); metabolism; mitochondrial unfolded protein response (UPRmt); mitophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1872885
  24. Biochim Biophys Acta Bioenerg. 2021 Jan 05. pii: S0005-2728(20)30215-2. [Epub ahead of print] 148365
    Szczepanowska K, Trifunovic A.
      Mitochondria are highly dynamic and stress-responsive organelles that are renewed, maintained and removed by a number of different mechanisms. Recent findings bring more evidence for the focused, defined, and regulatory function of the intramitochondrial proteases extending far beyond the traditional concepts of damage control and stress responses. Until recently, the macrodegradation processes, such as mitophagy, were promoted as the major regulator of OXPHOS remodelling and turnover. However, the spatiotemporal dynamics of the OXPHOS system can be greatly modulated by the intrinsic mitochondrial mechanisms acting apart from changes in the global mitochondrial dynamics. This, in turn, may substantially contribute to the shaping of the metabolic status of the cell.
    Keywords:  Mitochondrial respiratory chain; OXPHOS maintanance; OXPHOS turnover; mitochondrial proteases
    DOI:  https://doi.org/10.1016/j.bbabio.2020.148365
  25. Cell Metab. 2021 Jan 05. pii: S1550-4131(20)30666-5. [Epub ahead of print]33(1): 78-93.e7
    Li Z, Liu H, He J, Wang Z, Yin Z, You G, Wang Z, Davis RE, Lin P, Bergsagel PL, Manasanch EE, Wong STC, Esnaola NF, Chang JC, Orlowski RZ, Yi Q, Yang J.
      Obesity is often linked to malignancies including multiple myeloma, and the underlying mechanisms remain elusive. Here we showed that acetyl-CoA synthetase 2 (ACSS2) may be an important linker in obesity-related myeloma. ACSS2 is overexpressed in myeloma cells derived from obese patients and contributes to myeloma progression. We identified adipocyte-secreted angiotensin II as a direct cause of adiposity in increased ACSS2 expression. ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4), and enhances IRF4 stability and IRF4-mediated gene transcription through activation of acetylation. The importance of ACSS2 overexpression in myeloma is confirmed by the finding that an inhibitor of ACSS2 reduces myeloma growth both in vitro and in a diet-induced obese mouse model. Our findings demonstrate a key impact for obesity-induced ACSS2 on the progression of myeloma. Given the central role of ACSS2 in many tumors, this mechanism could be important to other obesity-related malignancies.
    Keywords:  ACSS2; IRF4; adipocytes; angiotensin II; autophagy; lysine acetylation; multiple myeloma; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.011
  26. Nat Commun. 2021 01 04. 12(1): 56
    Pickering KA, Gilroy K, Cassidy JW, Fey SK, Najumudeen AK, Zeiger LB, Vincent DF, Gay DM, Johansson J, Fordham RP, Miller B, Clark W, Hedley A, Unal EB, Kiel C, McGhee E, Machesky LM, Nixon C, Johnsson AE, Bain M, Strathdee D, van Hoof SR, Medema JP, Anderson KI, Brachmann SM, Stucke VM, Malliri A, Drysdale M, Turner M, Serrano L, Myant K, Campbell AD, Sansom OJ.
      RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
    DOI:  https://doi.org/10.1038/s41467-020-20255-4
  27. Cell Rep. 2021 Jan 05. pii: S2211-1247(20)31572-2. [Epub ahead of print]34(1): 108583
    Gnainsky Y, Zfanya N, Elgart M, Omri E, Brandis A, Mehlman T, Itkin M, Malitsky S, Adamski J, Soen Y.
      Gut microbiota have been shown to promote oogenesis and fecundity, but the mechanistic basis of remote influence on oogenesis remained unknown. Here, we report a systemic mechanism of influence mediated by bacterial-derived supply of mitochondrial coenzymes. Removal of microbiota decreased mitochondrial activity and ATP levels in the whole-body and ovary, resulting in repressed oogenesis. Similar repression was caused by RNA-based knockdown of mitochondrial function in ovarian follicle cells. Reduced mitochondrial function in germ-free (GF) females was reversed by bacterial recolonization or supplementation of riboflavin, a precursor of FAD and FMN. Metabolomics analysis of GF females revealed a decrease in oxidative phosphorylation and FAD levels and an increase in metabolites that are degraded by FAD-dependent enzymes (e.g., amino and fatty acids). Riboflavin supplementation opposed this effect, elevating mitochondrial function, ATP, and oogenesis. These findings uncover a bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction.
    Keywords:  Drosophila; metabolomics; microbiome; mitochondria; oogenesis; riboflavin
    DOI:  https://doi.org/10.1016/j.celrep.2020.108583
  28. Proc Natl Acad Sci U S A. 2021 Jan 26. pii: e2016778118. [Epub ahead of print]118(4):
    Levine ZG, Potter SC, Joiner CM, Fei GQ, Nabet B, Sonnett M, Zachara NE, Gray NS, Paulo JA, Walker S.
      O-GlcNAc transferase (OGT), found in the nucleus and cytoplasm of all mammalian cell types, is essential for cell proliferation. Why OGT is required for cell growth is not known. OGT performs two enzymatic reactions in the same active site. In one, it glycosylates thousands of different proteins, and in the other, it proteolytically cleaves another essential protein involved in gene expression. Deconvoluting OGT's myriad cellular roles has been challenging because genetic deletion is lethal; complementation methods have not been established. Here, we developed approaches to replace endogenous OGT with separation-of-function variants to investigate the importance of OGT's enzymatic activities for cell viability. Using genetic complementation, we found that OGT's glycosyltransferase function is required for cell growth but its protease function is dispensable. We next used complementation to construct a cell line with degron-tagged wild-type OGT. When OGT was degraded to very low levels, cells stopped proliferating but remained viable. Adding back catalytically inactive OGT rescued growth. Therefore, OGT has an essential noncatalytic role that is necessary for cell proliferation. By developing a method to quantify how OGT's catalytic and noncatalytic activities affect protein abundance, we found that OGT's noncatalytic functions often affect different proteins from its catalytic functions. Proteins involved in oxidative phosphorylation and the actin cytoskeleton were especially impacted by the noncatalytic functions. We conclude that OGT integrates both catalytic and noncatalytic functions to control cell physiology.
    Keywords:  HCF-1; O-GlcNAc transferase; OGT; cell proliferation; enzyme
    DOI:  https://doi.org/10.1073/pnas.2016778118
  29. Nat Commun. 2021 01 04. 12(1): 57
    Liu K, Sutter BM, Tu BP.
      Autophagy catabolizes cellular constituents to promote survival during nutrient deprivation. Yet, a metabolic comprehension of this recycling operation, despite its crucial importance, remains incomplete. Here, we uncover a specific metabolic function of autophagy that exquisitely adjusts cellular metabolism according to nitrogen availability in the budding yeast Saccharomyces cerevisiae. Autophagy enables metabolic plasticity to promote glutamate and aspartate synthesis, which empowers nitrogen-starved cells to replenish their nitrogen currency and sustain macromolecule synthesis. Our findings provide critical insights into the metabolic basis by which autophagy recycles cellular components and may also have important implications in understanding the role of autophagy in diseases such as cancer.
    DOI:  https://doi.org/10.1038/s41467-020-20253-6
  30. Cell Metab. 2021 Jan 05. pii: S1550-4131(20)30669-0. [Epub ahead of print]33(1): 1
    Evans A.
      
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.014
  31. Nat Commun. 2021 01 05. 12(1): 120
    Mühleip A, Kock Flygaard R, Ovciarikova J, Lacombe A, Fernandes P, Sheiner L, Amunts A.
      Mitochondrial ATP synthase plays a key role in inducing membrane curvature to establish cristae. In Apicomplexa causing diseases such as malaria and toxoplasmosis, an unusual cristae morphology has been observed, but its structural basis is unknown. Here, we report that the apicomplexan ATP synthase assembles into cyclic hexamers, essential to shape their distinct cristae. Cryo-EM was used to determine the structure of the hexamer, which is held together by interactions between parasite-specific subunits in the lumenal region. Overall, we identified 17 apicomplexan-specific subunits, and a minimal and nuclear-encoded subunit-a. The hexamer consists of three dimers with an extensive dimer interface that includes bound cardiolipins and the inhibitor IF1. Cryo-ET and subtomogram averaging revealed that hexamers arrange into ~20-megadalton pentagonal pyramids in the curved apical membrane regions. Knockout of the linker protein ATPTG11 resulted in the loss of pentagonal pyramids with concomitant aberrantly shaped cristae. Together, this demonstrates that the unique macromolecular arrangement is critical for the maintenance of cristae morphology in Apicomplexa.
    DOI:  https://doi.org/10.1038/s41467-020-20381-z
  32. Cell Calcium. 2021 Jan 02. pii: S0143-4160(20)30185-8. [Epub ahead of print]94 102343
    Barazzuol L, Giamogante F, Calì T.
      In the last decades, the communication between the Endoplasmic reticulum (ER) and mitochondria has obtained great attention: mitochondria-associated membranes (MAMs), which represent the contact sites between the two organelles, have indeed emerged as central hub involved in different fundamental cell processes, such as calcium signalling, apoptosis, autophagy and lipid biosynthesis. Consistently, dysregulation of ER-mitochondria crosstalk has been associated with different pathological conditions, ranging from diabetes to cancer and neurodegenerative diseases. In this review, we will try to summarize the current knowledge on MAMs' structure and functions in health and their relevance for human diseases.
    Keywords:  Calcium signaling; MAMs; Mitochondria; Neurodegeneration; Organelle contact sites
    DOI:  https://doi.org/10.1016/j.ceca.2020.102343
  33. Nat Immunol. 2021 Jan 04.
    Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, Peralta R, Wang Y, Wang Y, DePeaux K, Poholek AC, Delgoffe GM.
      Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.
    DOI:  https://doi.org/10.1038/s41590-020-00834-9
  34. Cancers (Basel). 2021 Jan 04. pii: E133. [Epub ahead of print]13(1):
    Lahalle A, Lacroix M, De Blasio C, Cissé MY, Linares LK, Le Cam L.
      The p53 pathway is functionally inactivated in most, if not all, human cancers. The p53 protein is a central effector of numerous stress-related molecular cascades. p53 controls a safeguard mechanism that prevents accumulation of abnormal cells and their transformation by regulating DNA repair, cell cycle progression, cell death, or senescence. The multiple cellular processes regulated by p53 were more recently extended to the control of metabolism and many studies support the notion that perturbations of p53-associated metabolic activities are linked to cancer development, as well as to other pathophysiological conditions including aging, type II diabetes, and liver disease. Although much less documented than p53 metabolic activities, converging lines of evidence indicate that other key components of this tumor suppressor pathway are also involved in cellular metabolism through p53-dependent as well as p53-independent mechanisms. Thus, at least from a metabolic standpoint, the p53 pathway must be considered as a non-linear pathway, but the complex metabolic network controlled by these p53 regulators and the mechanisms by which their activities are coordinated with p53 metabolic functions remain poorly understood. In this review, we highlight some of the metabolic pathways controlled by several central components of the p53 pathway and their role in tissue homeostasis, metabolic diseases, and cancer.
    Keywords:  aging; cancer; metabolic disease; metabolism; network; p53 pathway
    DOI:  https://doi.org/10.3390/cancers13010133
  35. Cancer Cell. 2020 Dec 31. pii: S1535-6108(20)30610-3. [Epub ahead of print]
    Boija A, Klein IA, Young RA.
      Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated-or will likely be implicated-in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer.
    Keywords:  biomolecular condensates; cancer; cancer therapeutics; dysregulated state; intrinsically disordered protein; phase separation
    DOI:  https://doi.org/10.1016/j.ccell.2020.12.003
  36. Int J Mol Sci. 2021 Jan 03. pii: E424. [Epub ahead of print]22(1):
    Avram VF, Chamkha I, Åsander-Frostner E, Ehinger JK, Timar RZ, Hansson MJ, Muntean DM, Elmér E.
      Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
    Keywords:  HepG2 cells; NV118; cell-permeable succinate; mitochondria; platelets; statins
    DOI:  https://doi.org/10.3390/ijms22010424
  37. Elife. 2021 Jan 08. pii: e60191. [Epub ahead of print]10
    Popay TM, Wang J, Adams CM, Howard GC, Codreanu SG, Sherrod SD, McLean JA, Thomas LR, Lorey SL, Machida YJ, Weissmiller AM, Eischen CM, Liu Q, Tansey WP.
      The oncoprotein transcription factor MYC is a major driver of malignancy and a highly validated but challenging target for the development of anticancer therapies. Novel strategies to inhibit MYC may come from understanding the co-factors it uses to drive pro-tumorigenic gene expression programs, providing their role in MYC activity is understood. Here we interrogate how one MYC co-factor, host cell factor (HCF)-1, contributes to MYC activity in a human Burkitt lymphoma setting. We identify genes connected to mitochondrial function and ribosome biogenesis as direct MYC/HCF-1 targets and demonstrate how modulation of the MYC-HCF-1 interaction influences cell growth, metabolite profiles, global gene expression patterns, and tumor growth in vivo. This work defines HCF-1 as a critical MYC co-factor, places the MYC-HCF-1 interaction in biological context, and highlights HCF-1 as a focal point for development of novel anti-MYC therapies.
    Keywords:  MYC; cancer; cancer biology; human; mouse; ribosome biogenesis
    DOI:  https://doi.org/10.7554/eLife.60191