bims-camemi 2020-02-16 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2020–02–16
forty-four papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

Mechanical regulation of glycolysis via cytoskeleton architecture.
Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.
The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models.
Dynamic 13C Flux Analysis Captures the Reorganization of Adipocyte Glucose Metabolism in Response to Insulin.
Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer.
Mitochondria-Associated Membranes (MAMs): A Novel Therapeutic Target for Treating Metabolic Syndrome.
Mitochondrial Calcium Regulation of Redox Signaling in Cancer.
Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration.
TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise.
Upregulation of ZNF148 in SDHB-deficient GIST potentiates FOXM1-mediated transcription and promotes tumor cell invasion.
Cell cycle regulators in cancer cell metabolism.
The selective autophagy receptor SQSTM1/p62 improves lifespan and proteostasis in an evolutionarily conserved manner.
Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle.
Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module.
A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity.
Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia.
GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling.
Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance.
Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition.
A Non-canonical Function of BMAL1 Metabolically Limits Obesity-Promoted Triple-Negative Breast Cancer.
The small molecule BI-2852 induces a nonfunctional dimer of KRAS.
Mechanisms of malignancy in glioblastoma cells are linked to MCU upregulation and higher intracellular calcium level.
Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination.
Single-Cell Transcriptome Atlas of Murine Endothelial Cells.
Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase.
Integration of mitochondrial energetics in heart with mathematical modelling.
Dynamic ROS Regulation by TIGAR: Balancing Anti-cancer and Pro-metastasis Effects.
Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study.
Mitoepigenetics and Its Emerging Roles in Cancer.
Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses.
Regulation of Nucleotide Metabolism and Germline Proliferation in Response to Nucleotide Imbalance and Genotoxic Stresses by EndoU Nuclease.
A gas chromatography-mass spectrometry (GC-MS) metabolomic approach in human colorectal cancer (CRC): the emerging role of monosaccharides and amino acids.
Energy Stress Inhibits Ferroptotic Cell Death via AMPK Activation.
IDH1-dependent α-KG regulates brown fat differentiation and function by modulating histone methylation.
Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.
MYCN amplification and ATRX mutations are incompatible in neuroblastoma.
Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution.
Proteogenomic Characterization of Endometrial Carcinoma.
O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.
Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy.
Regenerative lineages and immune-mediated pruning in lung cancer metastasis.
Oncogenic Kras driven metabolic reprogramming in pancreas cancer cells utilizes cytokines from the tumor microenvironment.
Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome.
Electrophiles Against (Skin) Diseases: More Than Nrf2.

Nature. 2020 Feb 12.

Mechanical regulation of glycolysis via cytoskeleton architecture.

Jin Suk Park, Christoph J Burckhardt, Rossana Lazcano, Luisa M Solis, Tadamoto Isogai, Linqing Li, Christopher S Chen, Boning Gao, John D Minna, Robert Bachoo, Ralph J DeBerardinis, Gaudenz Danuser.

The mechanics of the cellular microenvironment continuously modulates cell functions such as growth, survival, apoptosis, differentiation and morphogenesis via cytoskeletal remodelling and actomyosin contractility1-3. Although all of these processes consume energy4,5, it is unknown whether and how cells adapt their metabolic activity to variable mechanical cues. Here we report that the transfer of human bronchial epithelial cells from stiff to soft substrates causes a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by the disassembly of stress fibres, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress-fibre subset that is insensitive to substrate stiffness. Our data reveal a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumour tissue.

DOI: https://doi.org/10.1038/s41586-020-1998-1
Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30054-1. [Epub ahead of print]30(6): 1798-1810.e4

Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.

Nobu Oshima, Ryo Ishida, Shun Kishimoto, Kristin Beebe, Jeffrey R Brender, Kazutoshi Yamamoto, Daniel Urban, Ganesha Rai, Michelle S Johnson, Gloria Benavides, Giuseppe L Squadrito, Dan Crooks, Joseph Jackson, Abhinav Joshi, Bryan T Mott, Jonathan H Shrimp, Michael A Moses, Min-Jung Lee, Akira Yuno, Tobie D Lee, Xin Hu, Tamara Anderson, Donna Kusewitt, Helen H Hathaway, Ajit Jadhav, Didier Picard, Jane B Trepel, James B Mitchell, Gordon M Stott, William Moore, Anton Simeonov, Larry A Sklar, Jeffrey P Norenberg, W Marston Linehan, David J Maloney, Chi V Dang, Alex G Waterson, Matthew Hall, Victor M Darley-Usmar, Murali C Krishna, Leonard M Neckers.

  The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.

Keywords:  cancer; hyperpolarized magnetic resonance spectroscopic imaging; lactate dehydrogenase; metabolic flux; metabolic imaging; pyruvate metabolism

DOI:  https://doi.org/10.1016/j.celrep.2020.01.039
Sci Rep. 2020 Feb 14. 10(1): 2693

The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models.

Juliette J Lee, Simonetta Andreazza, Alexander J Whitworth.

Mutations in PINK1 and Parkin/PRKN cause the degeneration of dopaminergic neurons in familial forms of Parkinson's disease but the precise pathogenic mechanisms are unknown. The PINK1/Parkin pathway has been described to play a central role in mitochondrial homeostasis by signalling the targeted destruction of damaged mitochondria, however, how disrupting this process leads to neuronal death was unclear until recently. An elegant study in mice revealed that the loss of Pink1 or Prkn coupled with an additional mitochondrial stress resulted in the aberrant activation of the innate immune signalling, mediated via the cGAS/STING pathway, causing degeneration of dopaminergic neurons and motor impairment. Genetic knockout of Sting was sufficient to completely prevent neurodegeneration and accompanying motor deficits. To determine whether Sting plays a conserved role in Pink1/parkin related pathology, we tested for genetic interactions between Sting and Pink1/parkin in Drosophila. Surprisingly, we found that loss of Sting, or its downstream effector Relish, was insufficient to suppress the behavioural deficits or mitochondria disruption in the Pink1/parkin mutants. Thus, we conclude that phenotypes associated with loss of Pink1/parkin are not universally due to aberrant activation of the STING pathway.

DOI: https://doi.org/10.1038/s41598-020-59647-3
iScience. 2020 Jan 21. pii: S2589-0042(20)30038-9. [Epub ahead of print]23(2): 100855

Dynamic 13C Flux Analysis Captures the Reorganization of Adipocyte Glucose Metabolism in Response to Insulin.

Lake-Ee Quek, James R Krycer, Satoshi Ohno, Katsuyuki Yugi, Daniel J Fazakerley, Richard Scalzo, Sarah D Elkington, Ziwei Dai, Akiyoshi Hirayama, Satsuki Ikeda, Futaba Shoji, Kumi Suzuki, Jason W Locasale, Tomoyoshi Soga, David E James, Shinya Kuroda.

  Cellular metabolism is dynamic, but quantifying non-steady metabolic fluxes by stable isotope tracers presents unique computational challenges. Here, we developed an efficient 13C-tracer dynamic metabolic flux analysis (13C-DMFA) framework for modeling central carbon fluxes that vary over time. We used B-splines to generalize the flux parameterization system and to improve the stability of the optimization algorithm. As proof of concept, we investigated how 3T3-L1 cultured adipocytes acutely metabolize glucose in response to insulin. Insulin rapidly stimulates glucose uptake, but intracellular pathways responded with differing speeds and magnitudes. Fluxes in lower glycolysis increased faster than those in upper glycolysis. Glycolysis fluxes rose disproportionally larger and faster than the tricarboxylic acid cycle, with lactate a primary glucose end product. The uncovered array of flux dynamics suggests that glucose catabolism is additionally regulated beyond uptake to help shunt glucose into appropriate pathways. This work demonstrates the value of using dynamic intracellular fluxes to understand metabolic function and pathway regulation.

Keywords:  Biological Sciences; Flux Data; Metabolic Flux Analysis; Metabolomics

DOI:  https://doi.org/10.1016/j.isci.2020.100855
Cancer Cell. 2020 Feb 10. pii: S1535-6108(19)30581-1. [Epub ahead of print]37(2): 147-156

Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer.

Sharanya Sivanand, Matthew G Vander Heiden.

  Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.

Keywords:  branched-chain amino acids; cancer metabolism; epigenetics; metabolism

DOI:  https://doi.org/10.1016/j.ccell.2019.12.011
Curr Med Chem. 2020 Feb 11.

Mitochondria-Associated Membranes (MAMs): A Novel Therapeutic Target for Treating Metabolic Syndrome.

Ming Yang, Chenrui Li, Lin Sun.

  Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are the cellular structures that connect the ER and mitochondria and mediate communication between these two organelles. MAMs have been demonstrated to be involved in calcium signaling, lipid transfer, mitochondrial dynamic change, mitochondrial autophagy, and the ER stress response. In addition, MAMs are critical for metabolic regulation, and their dysfunction has been reported to be associated with metabolic syndrome, including the downregulation of insulin signaling and the accelerated progression of hyperlipidemia, obesity, and hypertension. This review covers the roles of MAMs in regulating insulin sensitivity and the molecular mechanism underlying MAM-regulated cellular metabolism and reveals the potential of MAMs as a therapeutic target in treating metabolic syndrome.

Keywords:  Diabetes; Endoplasmic reticulum; Insulin resistance; Metabolic syndrome; Mitochondria; Mitochondria-associated membrane (MAM)

DOI:  https://doi.org/10.2174/0929867327666200212100644
Cells. 2020 Feb 12. pii: E432. [Epub ahead of print]9(2):

Mitochondrial Calcium Regulation of Redox Signaling in Cancer.

Céline Delierneux, Sana Kouba, Santhanam Shanmughapriya, Marie Potier-Cartereau, Mohamed Trebak, Nadine Hempel.

  Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.

Keywords:  ROS; cancer; mitochondrial Ca2+ transport; mitochondrial ROS; redox signaling

DOI:  https://doi.org/10.3390/cells9020432
iScience. 2020 Jan 22. pii: S2589-0042(20)30041-9. [Epub ahead of print]23(2): 100858

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration.

Courtney Zasha Rumala, Juan Liu, Jason Wei Locasale, Barbara Ellen Corkey, Jude Thaddeus Deeney, Lucia Egydio Rameh.

  Chronic exposure of pancreatic β-cells to excess glucose can lead to metabolic acceleration and loss of stimulus-secretion coupling. Here, we examined how exposure to excess glucose (defined here as concentrations above 5 mM) affects mTORC1 signaling and the metabolism of β-cells. Acute exposure to excess glucose stimulated glycolysis-dependent mTORC1 signaling, without changes in the PI3K or AMPK pathways. Prolonged exposure to excess glucose led to hyperactivation of mTORC1 and metabolic acceleration, characterized by higher basal respiration and maximal respiratory capacity, increased energy demand, and enhanced flux through mitochondrial pyruvate metabolism. Inhibition of pyruvate transport to the mitochondria decelerated the metabolism of β-cells chronically exposed to excess glucose and re-established glucose-dependent mTORC1 signaling, disrupting a positive feedback loop for mTORC1 hyperactivation. mTOR inhibition had positive and negative impacts on various metabolic pathways and insulin secretion, demonstrating a role for mTOR signaling in the long-term metabolic adaptation of β-cells to excess glucose.

Keywords:  Diabetology; Endocrinology; Molecular Mechanism of Behavior; Specialized Functions of Cells

DOI:  https://doi.org/10.1016/j.isci.2020.100858
Nature. 2020 Feb 12.

TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise.

Yang Liu, Phong T Nguyen, Xun Wang, Yuting Zhao, Corbin E Meacham, Zhongju Zou, Bogdan Bordieanu, Manuel Johanns, Didier Vertommen, Tobias Wijshake, Herman May, Guanghua Xiao, Sanae Shoji-Kawata, Mark H Rider, Sean J Morrison, Prashant Mishra, Beth Levine.

The activation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle coordinates systemic metabolic responses to exercise1. Autophagy-a lysosomal degradation pathway that maintains cellular homeostasis2-is upregulated during exercise, and a core autophagy protein, beclin 1, is required for AMPK activation in skeletal muscle3. Here we describe a role for the innate immune-sensing molecule Toll-like receptor 9 (TLR9)4, and its interaction with beclin 1, in exercise-induced activation of AMPK in skeletal muscle. Mice that lack TLR9 are deficient in both exercise-induced activation of AMPK and plasma membrane localization of the GLUT4 glucose transporter in skeletal muscle, but are not deficient in autophagy. TLR9 binds beclin 1, and this interaction is increased by energy stress (glucose starvation and endurance exercise) and decreased by a BCL2 mutation3,5 that blocks the disruption of BCL2-beclin 1 binding. TLR9 regulates the assembly of the endolysosomal phosphatidylinositol 3-kinase complex (PI3KC3-C2)-which contains beclin 1 and UVRAG-in skeletal muscle during exercise, and knockout of beclin 1 or UVRAG inhibits the cellular AMPK activation induced by glucose starvation. Moreover, TLR9 functions in a muscle-autonomous fashion in ex vivo contraction-induced AMPK activation, glucose uptake and beclin 1-UVRAG complex assembly. These findings reveal a heretofore undescribed role for a Toll-like receptor in skeletal-muscle AMPK activation and glucose metabolism during exercise, as well as unexpected crosstalk between this innate immune sensor and autophagy proteins.

DOI: https://doi.org/10.1038/s41586-020-1992-7
Cancer Sci. 2020 Feb 14.

Upregulation of ZNF148 in SDHB-deficient GIST potentiates FOXM1-mediated transcription and promotes tumor cell invasion.

Xiaodong Gao, Chunmin Ma, Xiangwei Sun, Qin Zhao, Yong Fang, Yuhui Jiang, Kuntang Shen, Xian Shen.

  Succinate dehydrogenase (SDH) deficiency is associated with gastrointestinal stromal tumor (GIST) oncogenesis, while the underlying molecular mechanism remains to be further investigated. Here we show that succinate accumulation induced by SDHB loss-of-function increased expression of Zinc finger protein 148 (ZNF148, also named ZBP-89) in GIST cells. Meanwhile, ZNF148 is found to be phosphorylated by ERK at Ser306, and this phosphorylation results in ZNF148 binding to Forkhead box M1 (FOXM1). Through the complex formation at promoter, ZNF148 facilitates Histone H3 acetylation and FOXM1-mediated Snail transcription, which eventually promotes cell invasion and tumor growth. In consistence, the clinical analysis indicates SDHB deficiency is associated with elevated ZNF148 levels, and ZNF148-S306 phosphorylation level displays a positive correlation with poor prognosis in GIST patients. These findings illustrate an unidentified molecular mechanism underlying FOXM1-regulated gene transcription related to GIST cell invasion, which highlights the physiological effects of SDHB deficiency on invasiveness of GISTs.

Keywords:  ERK; GIST; Succinate dehydrogenase; ZNF148; phosphorylation

DOI:  https://doi.org/10.1111/cas.14348
Biochim Biophys Acta Mol Basis Dis. 2020 Feb 05. pii: S0925-4439(20)30060-0. [Epub ahead of print] 165715

Cell cycle regulators in cancer cell metabolism.

Lucia C Leal-Esteban, Lluis Fajas.

  Cancer proliferation and progression involves altered metabolic pathways as a result of continuous demand for energy and nutrients. In the last years, cell cycle regulators have been involved in the control of metabolic processes, such as glucose and insulin pathways and lipid synthesis, in addition to their canonical function controlling cell cycle progression. Here we describe recent data demonstrating the role of cell cycle regulators in the metabolic control especially in studies performed in cancer models. Moreover, we discuss the importance of these findings in the context of current cancer therapies to provide an overview of the relevance of targeting metabolism using inhibitors of the cell cycle regulation.

Keywords:  Cancer; Cell cycle; Cyclin-dependent kinases; Cyclins; Metabolic adaptation; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.bbadis.2020.165715
Autophagy. 2020 Feb 10. 1-3

The selective autophagy receptor SQSTM1/p62 improves lifespan and proteostasis in an evolutionarily conserved manner.

Ricardo Aparicio, Malene Hansen, David W Walker, Caroline Kumsta.

  The degradation of specific cargos such as ubiquitinated protein aggregates and dysfunctional mitochondria via macroautophagy/autophagy is facilitated by SQSTM1/p62, the first described selective autophagy receptor in metazoans. While the general process of autophagy plays crucial roles during aging, it remains unclear whether and how selective autophagy mediates effects on longevity and health. Two recent studies in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster observed gene expression changes of the respective SQSTM1 orthologs in response to environmental stressors or age and showed that overexpression of SQSTM1 is sufficient to extend lifespan and improve proteostasis and mitochondrial function in an autophagy-dependent manner in these model organisms. These findings show that increased expression of the selective autophagy receptor SQSTM1 is sufficient to induce aggrephagy in C. elegans, and mitophagy in Drosophila, and demonstrate an evolutionarily conserved role for SQSTM1 in lifespan determination.

Keywords:  Aging; C. elegans; Drosophila; SQST-1; SQSTM1; aggrephagy; heat shock; mitophagy; p62; proteostasis; ref(2)P; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2020.1725404
Cell Death Differ. 2020 Feb 10.

Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle.

Matteo Giovarelli, Silvia Zecchini, Emanuele Martini, Massimiliano Garrè, Sara Barozzi, Michela Ripolone, Laura Napoli, Marco Coazzoli, Chiara Vantaggiato, Paulina Roux-Biejat, Davide Cervia, Claudia Moscheni, Cristiana Perrotta, Dario Parazzoli, Emilio Clementi, Clara De Palma.

Mitochondria change distribution across cells following a variety of pathophysiological stimuli. The mechanisms presiding over this redistribution are yet undefined. In a murine model overexpressing Drp1 specifically in skeletal muscle, we find marked mitochondria repositioning in muscle fibres and we demonstrate that Drp1 is involved in this process. Drp1 binds KLC1 and enhances microtubule-dependent transport of mitochondria. Drp1-KLC1 coupling triggers the displacement of KIF5B from kinesin-1 complex increasing its binding to microtubule tracks and mitochondrial transport. High levels of Drp1 exacerbate this mechanism leading to the repositioning of mitochondria closer to nuclei. The reduction of Drp1 levels decreases kinesin-1 activation and induces the partial recovery of mitochondrial distribution. Drp1 overexpression is also associated with higher cyclin-dependent kinase-1 (Cdk-1) activation that promotes the persistent phosphorylation of desmin at Ser-31 and its disassembling. Fission inhibition has a positive effect on desmin Ser-31 phosphorylation, regardless of Cdk-1 activation, suggesting that induction of both fission and Cdk-1 are required for desmin collapse. This altered desmin architecture impairs mechanotransduction and compromises mitochondrial network stability priming mitochondria transport through microtubule-dependent trafficking with a mechanism that involves the Drp1-dependent regulation of kinesin-1 complex.

DOI: https://doi.org/10.1038/s41418-020-0510-7
Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30033-4. [Epub ahead of print]30(6): 1735-1752.e7

Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module.

Laura Di Magno, Simona Manni, Fiorella Di Pastena, Sonia Coni, Alberto Macone, Sara Cairoli, Manolo Sambucci, Paola Infante, Marta Moretti, Marialaura Petroni, Carmine Nicoletti, Carlo Capalbo, Enrico De Smaele, Lucia Di Marcotullio, Giuseppe Giannini, Luca Battistini, Bianca Maria Goffredo, Egidio Iorio, Enzo Agostinelli, Marella Maroder, Gianluca Canettieri.

  The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.

Keywords:  CtBP2; Hedgehog; NADH; biguanides; cancer; complex I; mGPD; metformin; phenformin; redox

DOI:  https://doi.org/10.1016/j.celrep.2020.01.024
Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30066-8. [Epub ahead of print]30(6): 1823-1834.e5

A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity.

Mitsuhiro Endoh, Masaya Baba, Tamie Endoh, Akiyoshi Hirayama, Ayako Nakamura-Ishizu, Terumasa Umemoto, Michihiro Hashimoto, Kunio Nagashima, Tomoyoshi Soga, Martin Lang, Laura S Schmidt, W Marston Linehan, Toshio Suda.

  The tumor suppressor folliculin (FLCN) suppresses nuclear translocation of TFE3, a master transcription factor for lysosomal biogenesis, via regulation of amino-acid-sensing Rag GTPases. However, the importance of this lysosomal regulation in mammalian physiology remains unclear. Following hematopoietic-lineage-specific Flcn deletion in mice, we found expansion of vacuolated phagocytes that accumulate glycogen in their cytoplasm, phenotypes reminiscent of lysosomal storage disorder (LSD). We report that TFE3 acts in a feedback loop to transcriptionally activate FLCN expression, and FLCN loss disrupts this loop, augmenting TFE3 activity. Tfe3 deletion in Flcn knockout mice reduces the number of phagocytes and ameliorates LSD-like phenotypes. We further reveal that TFE3 stimulates glycogenesis by promoting the expression of glycogenesis genes, including Gys1 and Gyg, upon loss of Flcn. Taken together, we propose that the FLCN-TFE3 feedback loop acts as a rheostat to control lysosome activity and prevents excessive glycogenesis and LSD-like phagocyte activation.

Keywords:  Birt-Hogg-Dubé Syndrome; Folliculin; Lysosomal storage disease; Lysosome; gluconeogenesis; glycogen; glycogenesis; hemophagocytosis

DOI:  https://doi.org/10.1016/j.celrep.2020.01.042
J Cell Mol Med. 2020 Feb 10.

Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia.

Marten Szibor, Rolf Schreckenberg, Zemfira Gizatullina, Eric Dufour, Marion Wiesnet, Praveen K Dhandapani, Grazyna Debska-Vielhaber, Juliana Heidler, Ilka Wittig, Tuula A Nyman, Ulrich Gärtner, Andrew R Hall, Victoria Pell, Carlo Viscomi, Thomas Krieg, Michael P Murphy, Thomas Braun, Frank N Gellerich, Klaus-Dieter Schlüter, Howard T Jacobs.

  Cardiac ischaemia-reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re-perfused post-ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post-anoxic heart mitochondria. However, post-ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up-regulated upon I/R such as the atrial natriuretic peptide (Anp) whilst expression of pro-fibrotic and pro-apoptotic transcripts were increased. Ex vivo analysis revealed contractile failure at nine but not 3 weeks after ischaemia whilst label-free quantitative proteomics identified an increase in proteins promoting adverse extracellular matrix remodelling. Together, this indicates an essential role for ETC-derived signals during cardiac adaptive remodelling and identified ROS as a possible effector.

Keywords:  adaptive cardiac remodelling; alternative oxidase; cardiac ischaemia-reperfusion; electron transport chain; mouse; reactive oxygen species

DOI:  https://doi.org/10.1111/jcmm.15043
JCI Insight. 2020 Feb 13. pii: 131596. [Epub ahead of print]5(3):

GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling.

Wen-Lian Chen, Xing Jin, Mingsong Wang, Dan Liu, Qin Luo, Hechuan Tian, Lili Cai, Lifei Meng, Rui Bi, Lei Wang, Xiao Xie, Guanzhen Yu, Lihui Li, Changsheng Dong, Qiliang Cai, Wei Jia, Wenyi Wei, Lijun Jia.

  Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 (SLC2A5). Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLC2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.

Keywords:  Lung cancer; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.131596
EMBO Rep. 2020 Feb 11. e49113

Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance.

Brandon J Berry, Adam J Trewin, Alexander S Milliken, Aksana Baldzizhar, Andrea M Amitrano, Yunki Lim, Minsoo Kim, Andrew P Wojtovich.

  Mitochondrial respiration generates an electrochemical proton gradient across the mitochondrial inner membrane called protonmotive force (PMF) to drive diverse functions and synthesize ATP. Current techniques to manipulate the PMF are limited to its dissipation; yet, there is no precise and reversible method to increase the PMF. To address this issue, we aimed to use an optogenetic approach and engineered a mitochondria-targeted light-activated proton pump that we name mitochondria-ON (mtON) to selectively increase the PMF in Caenorhabditis elegans. Here we show that mtON photoactivation increases the PMF in a dose-dependent manner, supports ATP synthesis, increases resistance to mitochondrial toxins, and modulates energy-sensing behavior. Moreover, transient mtON activation during hypoxic preconditioning prevents the well-characterized adaptive response of hypoxia resistance. Our results show that optogenetic manipulation of the PMF is a powerful tool to modulate metabolism and cell signaling.

Keywords:  anoxia; hypoxia; ischemia reperfusion; metabolism; uncoupling

DOI:  https://doi.org/10.15252/embr.201949113
Cell Stem Cell. 2020 Feb 10. pii: S1934-5909(20)30016-3. [Epub ahead of print]

Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition.

Ashwini Hinge, Jingyi He, James Bartram, Jose Javier, Juying Xu, Ellen Fjellman, Hiromi Sesaki, Tingyu Li, Jie Yu, Mark Wunderlich, James Mulloy, Matthew Kofron, Nathan Salomonis, H Leighton Grimes, Marie-Dominique Filippi.

The metabolic requirements of hematopoietic stem cells (HSCs) change with their cell cycle activity. However, the underlying role of mitochondria remains ill-defined. Here we found that, after mitochondrial activation with replication, HSCs irreversibly remodel the mitochondrial network and that this network is not repaired after HSC re-entry into quiescence, contrary to hematopoietic progenitors. HSCs keep and accumulate dysfunctional mitochondria through asymmetric segregation during active division. Mechanistically, mitochondria aggregate and depolarize after stress because of loss of activity of the mitochondrial fission regulator Drp1 onto mitochondria. Genetic and pharmacological studies indicate that inactivation of Drp1 causes loss of HSC regenerative potential while maintaining HSC quiescence. Molecularly, HSCs carrying dysfunctional mitochondria can re-enter quiescence but fail to synchronize the transcriptional control of core cell cycle and metabolic components in subsequent division. Thus, loss of fidelity of mitochondrial morphology and segregation is one type of HSC divisional memory and drives HSC attrition.

DOI: https://doi.org/10.1016/j.stem.2020.01.016
iScience. 2020 Jan 14. pii: S2589-0042(20)30022-5. [Epub ahead of print]23(2): 100839

A Non-canonical Function of BMAL1 Metabolically Limits Obesity-Promoted Triple-Negative Breast Cancer.

Cassandra A Ramos, Ching Ouyang, Yue Qi, Yiyin Chung, Chun-Ting Cheng, Mark A LaBarge, Victoria L Seewaldt, David K Ann.

  The epidemiological association between disrupted circadian rhythms and metabolic diseases is implicated in increased risk of human breast cancer and poor therapeutic outcomes. To define a metabolic phenotype and the underlying molecular mechanism, we applied chronic insulin treatment (CIT) to an in vitro model of triple-negative breast cancer to directly address how BMAL1, a key circadian transcription factor, regulates cancer cell respiration and governs tumor progression. At the cellular level, BMAL1 suppresses the flexibility of mitochondrial substrate usage and the pyruvate-dependent mitochondrial respiration induced by CIT. We established an animal model of diet-induced obesity/hyperinsulinemia and observed that BMAL1 functions as a tumor suppressor in obese, but not lean, mice. Downregulation of BMAL1 is associated with higher risk of metastasis in human breast tumors. In summary, loss of BMAL1 in tumors confers advantages to cancer cells in both intrinsic mitochondrial metabolism and extrinsic inflammatory tumor microenvironment during pre-diabetic obesity/hyperinsulinemia.

Keywords:  Biological Sciences; Cancer; Cell Biology; Chronobiology

DOI:  https://doi.org/10.1016/j.isci.2020.100839
Proc Natl Acad Sci U S A. 2020 Feb 11. pii: 201918164. [Epub ahead of print]

The small molecule BI-2852 induces a nonfunctional dimer of KRAS.

Timothy H Tran, Patrick Alexander, Srisathiyanarayanan Dharmaiah, Constance Agamasu, Dwight V Nissley, Frank McCormick, Dominic Esposito, Dhirendra K Simanshu, Andrew G Stephen, Trent E Balius.

DOI: https://doi.org/10.1073/pnas.1918164117
J Cell Sci. 2020 Feb 12. pii: jcs.237503. [Epub ahead of print]

Mechanisms of malignancy in glioblastoma cells are linked to MCU upregulation and higher intracellular calcium level.

Xiaoyun Li, Renza Spelat, Anna Bartolini, Daniela Cesselli, Tamara Ius, Miran Skrap, Federica Caponnetto, Ivana Manini, Yili Yang, Vincent Torre.

  Glioblastoma (GBM) is one of the most malignant brain tumours, and despite advances in treatment modalities, it remains largely incurable. Calcium regulation and dynamics play crucial roles in different aspects of cancer, but they have never been investigated in detail in GBM. Here, we report that spontaneous calcium waves in GBM cells cause unusual [Ca2+]i elevations (>1 µM), often propagating through tumour microtubes (TMs) connecting adjacent cells. This unusual [Ca2+]i elevation is not associated with the induction of cell death and is concomitant with overexpression of mitochondrial calcium uniporter (MCU). Here, we show that MCU silencing decreases proliferation and alters [Ca2+]i dynamics in U87 GBM cells, while MCU overexpression increases [Ca2+]i elevation in human astrocytes (HA). These results suggest that changes in the expression level of MCU, a protein involved in intracellular calcium regulation, influences GBM cell proliferation, contributing to GBM malignancy.

Keywords:  Calcium waves; Glioblastoma; MCU; Malignancy

DOI:  https://doi.org/10.1242/jcs.237503
Proc Natl Acad Sci U S A. 2020 Feb 11. pii: 201909814. [Epub ahead of print]

Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination.

Su Jin Ham, Daewon Lee, Heesuk Yoo, Kyoungho Jun, Heejin Shin, Jongkyeong Chung.

  VDAC1 is a critical substrate of Parkin responsible for the regulation of mitophagy and apoptosis. Here, we demonstrate that VDAC1 can be either mono- or polyubiquitinated by Parkin in a PINK1-dependent manner. VDAC1 deficient with polyubiquitination (VDAC1 Poly-KR) hampers mitophagy, but VDAC1 deficient with monoubiquitination (VDAC1 K274R) promotes apoptosis by augmenting the mitochondrial calcium uptake through the mitochondrial calcium uniporter (MCU) channel. The transgenic flies expressing Drosophila Porin K273R, corresponding to human VDAC1 K274R, show Parkinson disease (PD)-related phenotypes including locomotive dysfunction and degenerated dopaminergic neurons, which are relieved by suppressing MCU and mitochondrial calcium uptake. To further confirm the relevance of our findings in PD, we identify a missense mutation of Parkin discovered in PD patients, T415N, which lacks the ability to induce VDAC1 monoubiquitination but still maintains polyubiquitination. Interestingly, Drosophila Parkin T433N, corresponding to human Parkin T415N, fails to rescue the PD-related phenotypes of Parkin-null flies. Taken together, our results suggest that VDAC1 monoubiquitination plays important roles in the pathologies of PD by controlling apoptosis.

Keywords:  PINK1; Parkin; Parkinson disease; VDAC1; apoptosis

DOI:  https://doi.org/10.1073/pnas.1909814117
Cell. 2020 Feb 10. pii: S0092-8674(20)30062-3. [Epub ahead of print]

Single-Cell Transcriptome Atlas of Murine Endothelial Cells.

Joanna Kalucka, Laura P M H de Rooij, Jermaine Goveia, Katerina Rohlenova, Sébastien J Dumas, Elda Meta, Nadine V Conchinha, Federico Taverna, Laure-Anne Teuwen, Koen Veys, Melissa García-Caballero, Shawez Khan, Vincent Geldhof, Liliana Sokol, Rongyuan Chen, Lucas Treps, Mila Borri, Pauline de Zeeuw, Charlotte Dubois, Tobias K Karakach, Kim D Falkenberg, Magdalena Parys, Xiangke Yin, Stefan Vinckier, Yuxiang Du, Robert A Fenton, Luc Schoonjans, Mieke Dewerchin, Guy Eelen, Bernard Thienpont, Lin Lin, Lars Bolund, Xuri Li, Yonglun Luo, Peter Carmeliet.

  The heterogeneity of endothelial cells (ECs) across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomes from 11 mouse tissues and identified 78 EC subclusters, including Aqp7+ intestinal capillaries and angiogenic ECs in healthy tissues. ECs from brain/testis, liver/spleen, small intestine/colon, and skeletal muscle/heart pairwise expressed partially overlapping marker genes. Arterial, venous, and lymphatic ECs shared more markers in more tissues than did heterogeneous capillary ECs. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) exhibited transcriptome similarity across tissues, but the tissue (rather than the vessel) type contributed to the EC heterogeneity. Metabolic transcriptome analysis revealed a similar tissue-grouping phenomenon of ECs and heterogeneous metabolic gene signatures in ECs between tissues and between vascular beds within a single tissue in a tissue-type-dependent pattern. The EC atlas taxonomy enabled identification of EC subclusters in public scRNA-seq datasets and provides a powerful discovery tool and resource value.

Keywords:  endothelial metabolism; endothelial-cell heterogeneity; mouse endothelial atlas; single-cell RNA-seq

DOI:  https://doi.org/10.1016/j.cell.2020.01.015
Nat Commun. 2020 Feb 10. 11(1): 807

Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase.

Sangwon Byun, Sunmi Seok, Young-Chae Kim, Yang Zhang, Peter Yau, Naoki Iwamori, H Eric Xu, Jian Ma, Byron Kemper, Jongsook Kim Kemper.

Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.

DOI: https://doi.org/10.1038/s41467-020-14384-z
J Physiol. 2020 Feb 15.

Integration of mitochondrial energetics in heart with mathematical modelling.

Ayako Takeuchi, Satoshi Matsuoka.

  It has been an unsolved question how cardiac mitochondrial energetics is regulated during working transition. Mathematical modelling is a powerful tool to explore the complicated networks of mitochondrial metabolism. We summarise recent progress and remaining questions about mitochondrial energetics in heart, especially focusing on approaches utilizing mathematical modelling. Feedback activation by ADP and/or inorganic phosphate is an old, but still an attractive hypothesis for explaining regulation mechanisms of cardiac mitochondrial energetics. However, this hypothesis has not been fully validated by experiments, because rises of ADP and/or inorganic phosphate concentrations during cardiac workload increase have not been detected in many experiments. The hypothesis of intracellular energetic units is an extended version of feedback activation, which has a similar problem. The each-step activation hypothesis beautifully reproduces metabolites constancy, although such master regulators have not been identified yet. Ca2+ has been the most plausible candidate because some of the mitochondrial dehydrogenases are activated by Ca2+ . Recent experimental and simulation studies, however, throw doubt on its physiological relevance. Finally we discuss issues to be solved to obtain a better view of cardiac mitochondrial energetics. This article is protected by copyright. All rights reserved.

Keywords:  cardiac physiology; heart; mathematical model; muscle energetics

DOI:  https://doi.org/10.1113/JP276817
Cancer Cell. 2020 Feb 10. pii: S1535-6108(20)30048-9. [Epub ahead of print]37(2): 141-142

Dynamic ROS Regulation by TIGAR: Balancing Anti-cancer and Pro-metastasis Effects.

Sarah-Maria Fendt, Sophia Y Lunt.

The role of ROS in cancer is complex, with studies demonstrating both pro- and anti-tumor effects. In a pancreatic ductal adenocarcinoma model, ROS limitation through TIGAR has been shown to initially support cancer development but to later become a metabolic liability in metastasizing cells that is counteracted by decreased TIGAR expression.

DOI: https://doi.org/10.1016/j.ccell.2020.01.009
Gut. 2020 Feb 14. pii: gutjnl-2019-319811. [Epub ahead of print]

Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study.

Rachael Stolzenberg-Solomon, Andriy Derkach, Steven Moore, Stephanie J Weinstein, Demetrius Albanes, Joshua Sampson.

   OBJECTIVE: To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study.
DESIGN: We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis.
RESULTS: Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10-5). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter.
CONCLUSION: Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.

Keywords:  cancer epidemiology; epidemiology; pancreatic cancer

DOI:  https://doi.org/10.1136/gutjnl-2019-319811
Front Cell Dev Biol. 2020 ;8 4

Mitoepigenetics and Its Emerging Roles in Cancer.

Zhen Dong, Longjun Pu, Hongjuan Cui.

  In human beings, there is a ∼16,569 bp circular mitochondrial DNA (mtDNA) encoding 22 tRNAs, 12S and 16S rRNAs, 13 polypeptides that constitute the central core of ETC/OxPhos complexes, and some non-coding RNAs. Recently, mtDNA has been shown to have some covalent modifications such as methylation or hydroxylmethylation, which play pivotal epigenetic roles in mtDNA replication and transcription. Post-translational modifications of proteins in mitochondrial nucleoids such as mitochondrial transcription factor A (TFAM) also emerge as essential epigenetic modulations in mtDNA replication and transcription. Post-transcriptional modifications of mitochondrial RNAs (mtRNAs) including mt-rRNAs, mt-tRNAs and mt-mRNAs are important epigenetic modulations. Besides, mtDNA or nuclear DNA (n-DNA)-derived non-coding RNAs also play important roles in the regulation of translation and function of mitochondrial genes. These evidences introduce a novel concept of mitoepigenetics that refers to the study of modulations in the mitochondria that alter heritable phenotype in mitochondria itself without changing the mtDNA sequence. Since mitochondrial dysfunction contributes to carcinogenesis and tumor development, mitoepigenetics is also essential for cancer. Understanding the mode of actions of mitoepigenetics in cancers may shade light on the clinical diagnosis and prevention of these diseases. In this review, we summarize the present study about modifications in mtDNA, mtRNA and nucleoids and modulations of mtDNA/nDNA-derived non-coding RNAs that affect mtDNA translation/function, and overview recent studies of mitoepigenetic alterations in cancer.

Keywords:  cancer; mitoepigenetics; mtDNA methylation; mtRNA modification; non-coding RNAs

DOI:  https://doi.org/10.3389/fcell.2020.00004
Sci Transl Med. 2020 Feb 12. pii: eaax6337. [Epub ahead of print]12(530):

Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses.

Jesse M Jaynes, Rushikesh Sable, Michael Ronzetti, Wendy Bautista, Zachary Knotts, Abisola Abisoye-Ogunniyan, Dandan Li, Raul Calvo, Myagmarjav Dashnyam, Anju Singh, Theresa Guerin, Jason White, Sarangan Ravichandran, Parimal Kumar, Keyur Talsania, Vicky Chen, Anghesom Ghebremedhin, Balasubramanyam Karanam, Ahmad Bin Salam, Ruksana Amin, Taivan Odzorig, Taylor Aiken, Victoria Nguyen, Yansong Bian, Jelani C Zarif, Amber E de Groot, Monika Mehta, Lixin Fan, Xin Hu, Anton Simeonov, Nathan Pate, Mones Abu-Asab, Marc Ferrer, Noel Southall, Chan-Young Ock, Yongmei Zhao, Henry Lopez, Serguei Kozlov, Natalia de Val, Clayton C Yates, Bolormaa Baljinnyam, Juan Marugan, Udo Rudloff.

Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182-mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.

DOI: https://doi.org/10.1126/scitranslmed.aax6337
Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30075-9. [Epub ahead of print]30(6): 1848-1861.e5

Regulation of Nucleotide Metabolism and Germline Proliferation in Response to Nucleotide Imbalance and Genotoxic Stresses by EndoU Nuclease.

Fan Jia, Congwu Chi, Min Han.

  Nucleotide deprivation and imbalance present detrimental conditions for animals and are thus expected to trigger cellular responses that direct protective changes in metabolic, developmental, and behavioral programs, albeit such mechanisms are vastly underexplored. Following our previous finding that Caenorhabditis elegans shut down germ cell proliferation in response to pyrimidine deprivation, we find in this study that endonuclease ENDU-2 regulates nucleotide metabolism and germ cell proliferation in response to nucleotide imbalance and other genotoxic stress, and that it affects mitotic chromosomal segregation in the intestine and lifespan. ENDU-2 expression is induced by nucleotide imbalance and genotoxic stress, and ENDU-2 exerts its function in the intestine, mostly by inhibiting the phosphorylation of CTPS-1 through repressing the PKA pathway and histone deacetylase HDA-1. Human EndoU also affects the response to genotoxic drugs. Our work reveals an unknown role of ENDU-2 in regulating nucleotide metabolism and animals' response to genotoxic stress, which may link EndoU function to cancer treatment.

Keywords:  CTP synthase; CTPS phosphorylation; CTPS-1; ENDU-2; EndoU; cytidine deaminase; histone deacetylase; nucleotide imbalance; nucleotide sensing; protein kinase A

DOI:  https://doi.org/10.1016/j.celrep.2020.01.050
Ann Transl Med. 2019 Dec;7(23): 727

A gas chromatography-mass spectrometry (GC-MS) metabolomic approach in human colorectal cancer (CRC): the emerging role of monosaccharides and amino acids.

Luigi Barberini, Angelo Restivo, Antonio Noto, Simona Deidda, Claudia Fattuoni, Vassilios Fanos, Luca Saba, Luigi Zorcolo, Michele Mussap.

   Background: Colorectal cancer (CRC) has been confirmed to be the third most commonly diagnosed cancer in males and the second in females. We investigated the blood plasma metabolome in CRC patients and in healthy adults to elucidate the role of monosaccharides, amino acids, and their respective metabolic pathways as prognostic factors in patients with CRC.
Methods: Fifteen patients with CRC and nine healthy adults were enrolled in the study and their blood plasma samples analyzed by gas chromatography-mass spectrometry (GC-MS). Univariate Student's t-test, multivariate principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA) were conducted on MetaboAnalyst 4.0. The analysis of metabolic profiles was carried out by the web-based extension Metabolite Sets Enrichment Analysis (MSEA).
Results: Overall, 125 metabolites were identified in plasma samples by GC-MS. In CRC patient samples, nine metabolites, including D-mannose and fructose, were significantly more abundant than in controls; conversely, eleven amino derivatives were less abundant, including methionine, valine, lysine, and proline. Methionine was significantly less abundant in died patients compared with survivors. The most significantly altered metabolic pathways in CRC patients are those involving monosaccharides (primarily the catabolic pathway of fructose and D-mannose), and amino acids (primarily methionine, valine, leucine, and isoleucine).
Conclusions: The abundance of D-mannose in CRC patient samples contributes to inhibiting the growth of cancer cells, while the abundance of fructose may be consistent either with low consumption of fructose by aerobic glycolysis within cancer cells or with a high bioavailability of fructose from diet. The reduction in methionine concentration may be related to increased activity of the threonine and methionine catabolic pathways, confirmed by high levels of α-hydroxybutyrate.

Keywords:  Colorectal cancer (CRC); D-mannose; amino acids; metabolomics; methionine; monosaccharides

DOI:  https://doi.org/10.21037/atm.2019.12.34
Cancer Discov. 2020 Feb 14.

Energy Stress Inhibits Ferroptotic Cell Death via AMPK Activation.

In response to glucose starvation, AMPK inhibited lipid peroxidation-associated ferroptosis.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2020-023
Metabolism. 2020 Feb 05. pii: S0026-0495(20)30037-8. [Epub ahead of print] 154173

IDH1-dependent α-KG regulates brown fat differentiation and function by modulating histone methylation.

Hyun Sup Kang, Jae Ho Lee, Kyoung-Jin Oh, Eun Woo Lee, Baek Soo Han, Kun-Young Park, Jae Myoung Suh, Jeong-Ki Min, Seung-Wook Chi, Sang Chul Lee, Kwang-Hee Bae, Won Kon Kim.

   OBJECTIVE: Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood.
METHODS: We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development.
RESULTS: We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice.
CONCLUSION: These results suggested that the IDH1-α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.

Keywords:  Brown adipocyte differentiation; Histone modification; Isocitrate dehydrogenase 1 (IDH1); α-Ketoglutarate (α-KG)

DOI:  https://doi.org/10.1016/j.metabol.2020.154173
Nat Commun. 2020 Feb 14. 11(1): 900

Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.

Yun Liao, Junjie Zhao, Katarzyna Bulek, Fangqiang Tang, Xing Chen, Gang Cai, Shang Jia, Paul L Fox, Emina Huang, Theresa T Pizarro, Matthew F Kalady, Mark W Jackson, Shideng Bao, Ganes C Sen, George R Stark, Christopher J Chang, Xiaoxia Li.

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.

DOI: https://doi.org/10.1038/s41467-020-14698-y
Nat Commun. 2020 Feb 14. 11(1): 913

MYCN amplification and ATRX mutations are incompatible in neuroblastoma.

Maged Zeineldin, Sara Federico, Xiang Chen, Yiping Fan, Beisi Xu, Elizabeth Stewart, Xin Zhou, Jongrye Jeon, Lyra Griffiths, Rosa Nguyen, Jackie Norrie, John Easton, Heather Mulder, Donald Yergeau, Yanling Liu, Jianrong Wu, Collin Van Ryn, Arlene Naranjo, Michael D Hogarty, Marcin M Kamiński, Marc Valentine, Shondra M Pruett-Miller, Alberto Pappo, Jinghui Zhang, Michael R Clay, Armita Bahrami, Peter Vogel, Seungjae Lee, Anang Shelat, Jay F Sarthy, Michael P Meers, Rani E George, Elaine R Mardis, Richard K Wilson, Steven Henikoff, James R Downing, Michael A Dyer.

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex, and that induced by MYCN-mediated metabolic reprogramming, leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.

DOI: https://doi.org/10.1038/s41467-020-14682-6
Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30074-7. [Epub ahead of print]30(6): 1767-1779.e6

Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution.

Marie-Ming Aynaud, Olivier Mirabeau, Nadege Gruel, Sandrine Grossetête, Valentina Boeva, Simon Durand, Didier Surdez, Olivier Saulnier, Sakina Zaïdi, Svetlana Gribkova, Aziz Fouché, Ulykbek Kairov, Virginie Raynal, Franck Tirode, Thomas G P Grünewald, Mylene Bohec, Sylvain Baulande, Isabelle Janoueix-Lerosey, Jean-Philippe Vert, Emmanuel Barillot, Olivier Delattre, Andrei Zinovyev.

  EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive the heterogeneity of transcriptional programs. Here, we combine independent component analysis of single-cell RNA sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus define an exquisitely specific and direct enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation and strong oxidative phosphorylation metabolism are associated with a well-defined range of EWSR1-FLI1 activity. In contrast, a subpopulation of cells from below and above the intermediary EWSR1-FLI1 activity is characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within EwS tumors.

Keywords:  EWSR1-FLI1; Ewing sarcoma; Independent Component Analysis; intratumor heterogeneity; patient-derived xenografts; single-cell RNA-sequencing; time series; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2020.01.049
Cell. 2020 Feb 11. pii: S0092-8674(20)30107-0. [Epub ahead of print]

Proteogenomic Characterization of Endometrial Carcinoma.

Clinical Proteomic Tumor Analysis Consortium

  We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

Keywords:  CTNNB1; TP53; acetylation; circular RNA; endometrial cancer; endometrioid endometrial cancer; immune evasion; proteogenomics; proteomics; serous endometrial cancer

DOI:  https://doi.org/10.1016/j.cell.2020.01.026
Oncogenesis. 2020 Feb 14. 9(2): 21

O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.

Yinrui Lei, Tao Chen, Yeyi Li, Man Shang, Yan Zhang, Yuepeng Jin, Qiujing Yu, Fang Guo, Ting Wang.

The protein O-GlcNAcylation catalysed by O-GlcNAc transferase (OGT) is tightly regulated by glucose availability. It is upregulated and essential for tumor cell proliferation under hypoxic conditions. However, the mechanism behind is still unclear. Here, we showed that the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), which also promotes cell cycle progression in the nucleus, was O-GlcNAcylated in response to hypoxia. The O-GlcNAcylation of PFKFB3 could compete phosphorylation by hypoxia-activated ERK at the same modification site Ser172. Phosphorylated PFKFB3 could interact with the protein G3BP2 and retain in the cytosol; this in turn led to the accumulation of hypoxia-induced-P27 in the nucleus resulting in the cell cycle arrest. Such a pathway was compromised by high level of PFKFB3 O-GlcNAcylation in tumor cells contributing to cell cycle progression. Consistently, the PFKFB3-Ser172 phosphorylation level inversely correlated with the OGT level in pancreatic cancer patients. Our findings uncovered an O-GlcNAcylation mediated mechanism to promote tumor cell proliferation under metabolic stress, linking the aberrant OGT activity to tumorigenesis in pancreatic cancer.

DOI: https://doi.org/10.1038/s41389-020-0208-1
Sci Transl Med. 2020 Feb 12. pii: eaay8329. [Epub ahead of print]12(530):

Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy.

Jiang-Ping Song, Liang Chen, Xiao Chen, Jie Ren, Ning-Ning Zhang, Tiara Tirasawasdichai, Zhen-Liang Hu, Wei Hua, Yi-Ran Hu, Hui-Ru Tang, Huei-Sheng Vincent Chen, Sheng-Shou Hu.

Sudden death could be the first symptom of patients with arrhythmogenic cardiomyopathy (AC), a disease for which clinical indicators predicting adverse progression remain lacking. Recent findings suggest that metabolic dysregulation is present in AC. We performed this study to identify metabolic indicators that predicted major adverse cardiac events (MACEs) in patients with AC and their relatives. Comparing explanted hearts from patients with AC and healthy donors, we identified deregulated metabolic pathways using quantitative proteomics. Right ventricles (RVs) from patients with AC displayed elevated ketone metabolic enzymes, OXCT1 and HMGCS2, suggesting higher ketone metabolism in AC RVs. Analysis of matched coronary artery and sinus plasma suggested potential ketone body synthesis at early-stage AC, which was validated using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in vitro. Targeted metabolomics analysis in RVs from end-stage AC revealed a "burned-out" state, with predominant medium-chain fatty acid rather than ketone body utilization. In an independent validation cohort, 65 probands with mostly non-heart failure manifestations of AC had higher plasma β-hydroxybutyrate (β-OHB) than 62 healthy volunteers (P < 0.001). Probands with AC with MACE had higher β-OHB than those without MACE (P < 0.001). Among 94 relatives of probands, higher plasma β-OHB distinguished 25 relatives having suspected AC from nonaffected relatives. This study demonstrates that elevated plasma β-OHB predicts MACE in probands and disease progression in patients with AC and their clinically asymptomatic relatives.

DOI: https://doi.org/10.1126/scitranslmed.aay8329
Nat Med. 2020 Feb;26(2): 259-269

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Ashley M Laughney, Jing Hu, Nathaniel R Campbell, Samuel F Bakhoum, Manu Setty, Vincent-Philippe Lavallée, Yubin Xie, Ignas Masilionis, Ambrose J Carr, Sanjay Kottapalli, Viola Allaj, Marissa Mattar, Natasha Rekhtman, Joao B Xavier, Linas Mazutis, John T Poirier, Charles M Rudin, Dana Pe'er, Joan Massagué.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.

DOI: https://doi.org/10.1038/s41591-019-0750-6
Cancer Discov. 2020 Feb 11. pii: CD-19-0297. [Epub ahead of print]

Oncogenic Kras driven metabolic reprogramming in pancreas cancer cells utilizes cytokines from the tumor microenvironment.

Prasenjit Dey, Jun Li, Jianhua Zhang, Surendra Chaurasiya, Anders Strom, Huamin Wang, Wen-Ting Liao, Frederick Cavallaro, Parker Denz, Vincent Bernard, Er-Yen Yen, Giannicola Genovese, Pat Gulhati, Jielin Liu, Deepavali Chakravarti, Pingna Deng, Tingxin Zhang, Federica Carbone, Qing Chang, Haoqiang Ying, Xiaoying Shang, Denise J Spring, Bidyut Ghosh, Nagireddy Putluri, Anirban Maitra, Y Alan Wang, Ronald A DePinho.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic Kras in pro-tumorigenic signaling interactions between cancer cells and host cells. We show that Kras* drives cell autonomous expression of type I cytokine receptor complexes (IL2ry-IL4ra and IL2ry-IL13ra1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading TH2 cells in the microenvironment. Early neoplastic lesions show close proximity of Kras* cancer cells and TH2 cells producing IL4 and IL13. Activated IL2ry-IL4ra and IL2ry-IL13ra1 receptors signal primarily via Jak1-Stat6. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC.

DOI: https://doi.org/10.1158/2159-8290.CD-19-0297
Proc Natl Acad Sci U S A. 2020 Feb 11. pii: 201911998. [Epub ahead of print]

Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome.

Hong Lin, Xiaozhe Zhang, Li Liu, Qiuyu Fu, Chuanlong Zang, Yan Ding, Yang Su, Zhixue Xu, Sining He, Xiaoli Yang, Xiayun Wei, Haibin Mao, Yasong Cui, Yi Wei, Chuanzheng Zhou, Lilin Du, Niu Huang, Ning Zheng, Tao Wang, Feng Rao.

  The Cullin-RING ligases (CRLs) are the largest family of ubiquitin E3s activated by neddylation and regulated by the deneddylase COP9 signalosome (CSN). The inositol polyphosphate metabolites promote the formation of CRL-CSN complexes, but with unclear mechanism of action. Here, we provide structural and genetic evidence supporting inositol hexakisphosphate (IP6) as a general CSN cofactor recruiting CRLs. We determined the crystal structure of IP6 in complex with CSN subunit 2 (CSN2), based on which we identified the IP6-corresponding electron density in the cryoelectron microscopy map of a CRL4A-CSN complex. IP6 binds to a cognate pocket formed by conserved lysine residues from CSN2 and Rbx1/Roc1, thereby strengthening CRL-CSN interactions to dislodge the E2 CDC34/UBE2R from CRL and to promote CRL deneddylation. IP6 binding-deficient Csn2 K70E/K70E knockin mice are embryonic lethal. The same mutation disabled Schizosaccharomyces pombe Csn2 from rescuing UV-hypersensitivity of csn2-null yeast. These data suggest that CRL transition from the E2-bound active state to the CSN-bound sequestered state is critically assisted by an interfacial IP6 small molecule, whose metabolism may be coupled to CRL-CSN complex dynamics.

Keywords:  COP9 signalosome; Cullin-RING ligases; deneddylation; inositol hexakisphosphate; intermolecular glue

DOI:  https://doi.org/10.1073/pnas.1911998117
Biomolecules. 2020 Feb 11. pii: E271. [Epub ahead of print]10(2):

Electrophiles Against (Skin) Diseases: More Than Nrf2.

Paulina Hennig, Gabriele Fenini, Michela Di Filippo, Hans-Dietmar Beer.

  The skin represents an indispensable barrier between the organism and the environment and is the first line of defense against exogenous insults. The transcription factor NRF2 is a central regulator of cytoprotection and stress resistance. NRF2 is activated in response to oxidative stress by reactive oxygen species (ROS) and electrophiles. These electrophiles oxidize specific cysteine residues of the NRF2 inhibitor KEAP1, leading to KEAP1 inactivation and, subsequently, NRF2 activation. As oxidative stress is associated with inflammation, the NRF2 pathway plays important roles in the pathogenesis of common inflammatory diseases and cancer in many tissues and organs, including the skin. The electrophile and NRF2 activator dimethyl fumarate (DMF) is an established and efficient drug for patients suffering from the common inflammatory skin disease psoriasis and the neuro-inflammatory disease multiple sclerosis (MS). In this review, we discuss possible molecular mechanisms underlying the therapeutic activity of DMF and other NRF2 activators. Recent evidence suggests that electrophiles not only activate NRF2, but also target other inflammation-associated pathways including the transcription factor NF-κB and the multi-protein complexes termed inflammasomes. Inflammasomes are central regulators of inflammation and are involved in many inflammatory conditions. Most importantly, the NRF2 and inflammasome pathways are connected at different levels, mainly antagonistically.

Keywords:  DMF; NF-κB; NRF2; electrophile; inflammasomes; inflammation; skin

DOI:  https://doi.org/10.3390/biom10020271