bims-camemi 2023-07-30 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023‒07‒30
forty-four papers selected by
Christian Frezza, Universität zu Köln

Branched-chain amino acid synthesis is coupled to TOR activation early in the cell cycle in yeast.
Alkaline intracellular pH (pHi) increases PI3K kinase activity to promote mTORC1 and mTORC2 signaling and function during growth factor limitation.
Modeling epigenetic lesions that cause gliomas.
Mitochondrial Magnesium is the cationic rheostat for MCU-mediated mitochondrial Ca2+ uptake.
Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation.
Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells.
Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.
Assembly of mitochondrial succinate dehydrogenase in human health and disease.
Glucose controls glucagon secretion by regulating fatty acid oxidation in pancreatic alpha cells.
De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.
Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.
The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis.
Evolutionarily divergent mTOR remodels translatome for tissue regeneration.
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.
Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.
Intracellular Energy Production and Distribution in Hypoxia.
3-hydroxykynurenine is a ROS-inducing cytotoxic tryptophan metabolite that disrupts the TCA cycle.
mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching.
Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells.
Searching for molecular hypoxia sensors among oxygen-dependent enzymes.
Lactate modulates iron metabolism by binding soluble adenylyl cyclase.
Fetal orchestration of maternal metabolism via IGF2.
FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy.
The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth.
PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics.
Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement.
Reciprocal regulation between the molecular clock and kidney injury.
The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates.
Cancers make their own luck: theories of cancer origins.
Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.
Linear Response Theory of Evolved Metabolic Systems.
Rewiring cancer drivers to activate apoptosis.
On the origin and evolution of the dual oscillator model underlying the photoperiodic clockwork in the suprachiasmatic nucleus.
Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.
Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome.
A Cell Cycle-Dependent Ferroptosis Sensitivity Switch Governed by EMP2.
Biosynthesis, Deficiency, and Supplementation of Coenzyme Q.
Interleukin-17 as a key player in neuroimmunometabolism.
Platelet-derived lipids promote insulin secretion of pancreatic β cells.
Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.
Leveraging translational insights toward precision medicine approaches for brain metastases.
Evolutionary histories of breast cancer and related clones.
Control of protein synthesis through mRNA pseudouridylation by dyskerin.
ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism.

EMBO Rep. 2023 Jul 27. e57372

Branched-chain amino acid synthesis is coupled to TOR activation early in the cell cycle in yeast.

Heidi M Blank, Carsten Reuse, Kerstin Schmidt-Hohagen, Staci E Hammer, Karsten Hiller, Michael Polymenis.

  How cells coordinate their metabolism with division determines the rate of cell proliferation. Dynamic patterns of metabolite synthesis during the cell cycle are unexplored. We report the first isotope tracing analysis in synchronous, growing budding yeast cells. Synthesis of leucine, a branched-chain amino acid (BCAA), increases through the G1 phase of the cell cycle, peaking later during DNA replication. Cells lacking Bat1, a mitochondrial aminotransferase that synthesizes BCAAs, grow slower, are smaller, and are delayed in the G1 phase, phenocopying cells in which the growth-promoting kinase complex TORC1 is moderately inhibited. Loss of Bat1 lowers the levels of BCAAs and reduces TORC1 activity. Exogenous provision of valine and, to a lesser extent, leucine to cells lacking Bat1 promotes cell division. Valine addition also increases TORC1 activity. In wild-type cells, TORC1 activity is dynamic in the cell cycle, starting low in early G1 but increasing later in the cell cycle. These results suggest a link between BCAA synthesis from glucose to TORC1 activation in the G1 phase of the cell cycle.

Keywords:  BCAA; BCAT; TORC1; cell size; isotope tracing

DOI:  https://doi.org/10.15252/embr.202357372
J Biol Chem. 2023 Jul 26. pii: S0021-9258(23)02125-7. [Epub ahead of print] 105097

Alkaline intracellular pH (pHi) increases PI3K kinase activity to promote mTORC1 and mTORC2 signaling and function during growth factor limitation.

Dubek Kazyken, Stephen I Lentz, Maxwell Wadley, Diane C Fingar.

  The conserved protein kinase mTOR (mechanistic target of rapamycin) responds to diverse environmental cues to control cell metabolism and promote cell growth, proliferation, and survival as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTORC2. Our prior work demonstrated that an alkaline intracellular pH (pHi) increases mTORC2 activity and cell survival in complete media in part by activating AMPK, a kinase best known to sense energetic stress. It is important to note that an alkaline pHi represents an under-appreciated hallmark of cancer cells that promotes their oncogenic behaviors. In addition, mechanisms that control mTORC1 and mTORC2 signaling and function remain incompletely defined, particularly in response to stress conditions. Here, we demonstrate that an alkaline pHi increases PI3K activity to promote mTORC1 and mTORC2 signaling in the absence of serum growth factors. Alkaline pHi increases mTORC1 activity through PI3K-Akt signaling, which mediates inhibitory phosphorylation of the upstream proteins TSC2 and PRAS40 and dissociates TSC2 from lysosomal membranes, thus enabling Rheb-mediated activation of mTORC1. Thus, we show that an alkaline pHi mimics growth factor-PI3K signaling. Functionally, we also demonstrate that an alkaline pHi increases cap-dependent protein synthesis through inhibitory phosphorylation of 4EBP1 and suppresses apoptosis in a PI3K- and mTOR-dependent manner. We speculate that an alkaline pHi promotes a low, basal level of cell metabolism (e.g., protein synthesis) that enables cancer cells within growing tumors to proliferate and survive despite limiting growth factors and nutrients, in part through elevated PI3K-mTORC1 and/or PI3K-mTORC2 signaling.

Keywords:  Akt PKB; S6 kinase; apoptosis; cell signaling; eukaryotic translation initiation factor 4E (eIF4E); eukaryotic translation initiation factor 4E-binding protein (eIF4EBP1); pH regulation; phosphatidylinositide 3-kinase (PI 3-kinase); protein synthesis; target of rapamycin (TOR)

DOI:  https://doi.org/10.1016/j.jbc.2023.105097
Cell. 2023 Jul 20. pii: S0092-8674(23)00729-8. [Epub ahead of print]

Modeling epigenetic lesions that cause gliomas.

Gilbert J Rahme, Nauman M Javed, Kaitlyn L Puorro, Shouhui Xin, Volker Hovestadt, Sarah E Johnstone, Bradley E Bernstein.

  Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.

Keywords:  CDKN2A; DNA methylation; IDH mutation; PDGFRA; cell of origin; chromatin; genome topology; glioma; nuclear architecture; oligodendrocyte progenitor cells

DOI:  https://doi.org/10.1016/j.cell.2023.06.022
Res Sq. 2023 Jul 18. pii: rs.3.rs-3088175. [Epub ahead of print]

Mitochondrial Magnesium is the cationic rheostat for MCU-mediated mitochondrial Ca2+ uptake.

Santhanam Shanmughapriya, Thiruvelselvan Ponnusamy, Prema Velusamy, Amrendra Kumar, Daniel Morris, Xueqian Zhang, Gang Ning, Marianne Klinger, Jean Copper, Sudarsan Rajan, Joseph Cheung, Natarajaseenivasan Kalimuthusamy, Nelli Mnatsakanyan.

Calcium (Ca2+) uptake by mitochondria is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. MCU is a hetero-oligomeric complex with a pore-forming component and accessory proteins required for channel activity. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed Mrs2 as the authentic mammalian mitochondrial Mg2+ channel using the planar lipid bilayer recordings. Using a liver-specific Mrs2 KO mouse model, we showed that decreased matrix [Mg2+] is associated with increased MCU activity and matrix Ca2+ overload. The disruption of Mg2+-dependent MCU regulation significantly prompted mitochondrial permeability transition pore opening-mediated cell death during tissue IR injury. Our findings support a critical role for mMg2+ in regulating MCU activity and attenuating mCa2+ overload.

DOI: https://doi.org/10.21203/rs.3.rs-3088175/v1
Dev Cell. 2023 Jul 18. pii: S1534-5807(23)00331-3. [Epub ahead of print]

Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation.

Melissa A Roberts, Kirandeep K Deol, Alyssa J Mathiowetz, Mike Lange, Dara E Leto, Julian Stevenson, Sayed Hadi Hashemi, David W Morgens, Emilee Easter, Kartoosh Heydari, Mike A Nalls, Michael C Bassik, Martin Kampmann, Ron R Kopito, Faraz Faghri, James A Olzmann.

  Despite the key roles of perilipin-2 (PLIN2) in governing lipid droplet (LD) metabolism, the mechanisms that regulate PLIN2 levels remain incompletely understood. Here, we leverage a set of genome-edited human PLIN2 reporter cell lines in a series of CRISPR-Cas9 loss-of-function screens, identifying genetic modifiers that influence PLIN2 expression and post-translational stability under different metabolic conditions and in different cell types. These regulators include canonical genes that control lipid metabolism as well as genes involved in ubiquitination, transcription, and mitochondrial function. We further demonstrate a role for the E3 ligase MARCH6 in regulating triacylglycerol biosynthesis, thereby influencing LD abundance and PLIN2 stability. Finally, our CRISPR screens and several published screens provide the foundation for CRISPRlipid (http://crisprlipid.org), an online data commons for lipid-related functional genomics data. Our study identifies mechanisms of PLIN2 and LD regulation and provides an extensive resource for the exploration of LD biology and lipid metabolism.

Keywords:  CRISPR; ERAD; MARCH6; PLIN2; endoplasmic reticulum; genetic screen; lipid droplet; metabolism; perilipin; resource

DOI:  https://doi.org/10.1016/j.devcel.2023.07.001
J Biol Chem. 2023 Jul 20. pii: S0021-9258(23)02103-8. [Epub ahead of print] 105075

Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells.

Pallavi R Joshi, Shayan Sadre, Xiaoyan A Guo, Jason G McCoy, Vamsi K Mootha.

  Iron sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC containing proteins are the ferredoxin family of electron carriers. Humans have two ferredoxins, FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but ferredoxins were not included in that study. Here we report that FDX1, but not FDX2, is dispensable under 1% O2 in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC containing enzyme lipoyl synthase (LIAS). While hypoxia can rescue the growth phenotype of either FDX1 or LIAS knockout cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.

Keywords:  Energy Metabolism; Hypoxia; Iron-Sulfur Protein; Lipoate; Mitochondria; S-adenosyl methionine

DOI:  https://doi.org/10.1016/j.jbc.2023.105075
Nat Commun. 2023 07 25. 14(1): 4101

Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Liming Yu, Lin Xu, Haiyan Chu, Jun Peng, Anastasia Sacharidou, Hsi-Hsien Hsieh, Ada Weinstock, Sohaib Khan, Liqian Ma, José Gabriel Barcia Durán, Jeffrey McDonald, Erik R Nelson, Sunghee Park, Donald P McDonnell, Kathryn J Moore, Lily Jun-Shen Huang, Edward A Fisher, Chieko Mineo, Linzhang Huang, Philip W Shaul.

Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.

DOI: https://doi.org/10.1038/s41467-023-39586-z
Free Radic Biol Med. 2023 Jul 23. pii: S0891-5849(23)00552-X. [Epub ahead of print]

Assembly of mitochondrial succinate dehydrogenase in human health and disease.

Ke Cao, Jie Xu, Wenli Cao, Xueqiang Wang, Weiqiang Lv, Mengqi Zeng, Xuan Zou, Jiankang Liu, Zhihui Feng.

  Mitochondrial succinate dehydrogenase (SDH), also known as electron transport chain (ETC) Complex II, is the only enzyme complex engaged in both oxidative phosphorylation and the tricarboxylic acid (TCA) cycle. SDH has received increasing attention due to its crucial role in regulating mitochondrial metabolism and human health. Despite having the fewest subunits among the four ETC complexes, functional SDH is formed via a sequential and well-coordinated assembly of subunits. Along with the discovery of subunit-specific assembly factors, the dynamic involvement of the SDH assembly process in a broad range of diseases has been revealed. Recently, we reported that perturbation of SDH assembly in different tissues leads to interesting and distinct pathophysiological changes in mice, indicating a need to understand the intricate SDH assembly process in human health and diseases. Thus, in this review, we summarize recent findings on SDH pathogenesis with respect to disease and a focus on SDH assembly.

Keywords:  Mitochondria; Succinate dehydrogenase; Succinate dehydrogenase assembly factors; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.07.023
Diabetes. 2023 Jul 26. pii: db230056. [Epub ahead of print]

Glucose controls glucagon secretion by regulating fatty acid oxidation in pancreatic alpha cells.

Sarah L Armour, Alexander Frueh, Margarita V Chibalina, Haiqiang Dou, Lidia Argemi-Muntadas, Alexander Hamiltion, Georgios Katzilieris-Petras, Peter Carmeliet, Benjamin Davies, Thomas Moritz, Lena Eliasson, Patrik Rorsman, Jakob G Knudsen.

Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from α-cells to stimulate hepatic glucose production. However, the mechanisms that regulate glucagon secretion from pancreatic α-cells remain unclear. Here we show that in α-cells the interaction between fatty acid oxidation and glucose metabolism controls glucagon secretion. The glucose dependent inhibition of glucagon secretion relies on pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity and lowering of mitochondrial fatty acid oxidation by increases in glucose. This results in reduced intracellular ATP and leads to membrane repolarisation and inhibition of glucagon secretion. These findings provide a new framework for the metabolic regulation of the α-cell, where regulation of fatty acid oxidation by glucose accounts for the stimulation and inhibition of glucagon secretion.

DOI: https://doi.org/10.2337/db23-0056
bioRxiv. 2023 Jul 15. pii: 2023.07.15.549149. [Epub ahead of print]

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

Naveen Kumar Tangudu, Raquel Buj, Jiefei Wang, Aidan R Cole, Apoorva Uboveja, Richard Fang, Amandine Amalric, Maureen A Lyons, Uma R Chandran, Katherine M Aird.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ∼50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic repro-gramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. Whether other nucleotide metabolic genes and pathways are affected by p16/ CDKN2A loss and if these can be specifically targeted in p16-low tumors has not been previously explored. Using CRISPR KO libraries in multiple isogenic melanoma cell lines with wildtype p16/ CDKN2A and p16/ CDKN2A knockdown, we determined that many nucleotide metabolism genes are negatively enriched in p16/ CDKN2A knockdown cells compared to controls. Indeed, many of the genes that are required for survival in the context of low p16/ CDKN2A expression based on our CRISPR screens are upregulated in p16/ CDKN2A knockdown melanoma cells and those with endogenously low CDKN2A expression. We determined that cells with low p16 expression are sensitive to multiple inhibitors of de novo purine synthesis in vitro by inducing apoptosis. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16-low tumors as loss of p16 may provide a therapeutic window for these agents.

DOI: https://doi.org/10.1101/2023.07.15.549149
Genome Res. 2023 Jul 24. pii: gr.277755.123. [Epub ahead of print]

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

Rosario Avolio, Ilenia Agliarulo, Daniela Criscuolo, Daniela Sarnataro, Margherita Auriemma, Sabrina De Lella, Sara Pennacchio, Giovanni Calice, Martin Y Ng, Carlotta Giorgi, Paolo Pinton, Barry Cooperman, Matteo Landriscina, Franca Esposito, Danilo Swann Matassa.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

DOI: https://doi.org/10.1101/gr.277755.123
Cell Metab. 2023 Jul 20. pii: S1550-4131(23)00250-4. [Epub ahead of print]

The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis.

Liraz Shmuel-Galia, Fiachra Humphries, Tim Vierbuchen, Zhaozhao Jiang, Nolan Santos, John Johnson, Boris Shklyar, Leonel Joannas, Nicholas Mustone, Shany Sherman, Doyle Ward, JeanMarie Houghton, Christina E Baer, Aisling O'Hara, Jorge Henao-Mejia, Kasper Hoebe, Katherine A Fitzgerald.

  This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS). As a result, HOXA11os-deficient mice develop spontaneous intestinal inflammation and are hypersusceptible to colitis. Collectively, these studies identify a new regulatory axis whereby a lncRNA maintains intestinal homeostasis and restricts inflammation in the colon through the regulation of complex I activity.

Keywords:  IBD; Krebs cycle; OXPHOS; colitis; complex I; intestinal inflammation; lncRNA; mitochondria; mtROS; mucosal inflammation; ncRNA

DOI:  https://doi.org/10.1016/j.cmet.2023.06.019
Nature. 2023 Jul 26.

Evolutionarily divergent mTOR remodels translatome for tissue regeneration.

Olena Zhulyn, Hannah D Rosenblatt, Leila Shokat, Shizhong Dai, Duygu Kuzuoglu-Öztürk, Zijian Zhang, Davide Ruggero, Kevan M Shokat, Maria Barna.

An outstanding mystery in biology is why some species, such as the axolotl, can regenerate tissues whereas mammals cannot1. Here, we demonstrate that rapid activation of protein synthesis is a unique feature of the injury response critical for limb regeneration in the axolotl (Ambystoma mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components that are selectively activated at the level of translation from pre-existing messenger RNAs in response to injury. By contrast, protein synthesis is not activated in response to non-regenerative digit amputation in the mouse. We identify the mTORC1 pathway as a key upstream signal that mediates tissue regeneration and translational control in the axolotl. We discover unique expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR (axmTOR) in human cells, we show that these changes create a hypersensitive kinase that allows axolotls to maintain this pathway in a highly labile state primed for rapid activation. This change renders axolotl mTOR more sensitive to nutrient sensing, and inhibition of amino acid transport is sufficient to inhibit tissue regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in a highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.

DOI: https://doi.org/10.1038/s41586-023-06365-1
Nat Struct Mol Biol. 2023 Jul 24.

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.

Yuxiang Zhang, David Remillard, Ugoma Onubogu, Barbara Karakyriakou, Joshua N Asiaban, Anissa R Ramos, Kirsten Bowland, Timothy R Bishop, Paige A Barta, Stephanie Nance, Adam D Durbin, Christopher J Ott, Michalina Janiszewska, Benjamin F Cravatt, Michael A Erb.

Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2-NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1/2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.

DOI: https://doi.org/10.1038/s41594-023-01041-4
Cell Genom. 2023 Jul 12. 3(7): 100321

Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.

Samantha M Bevill, Salvador Casaní-Galdón, Chadi A El Farran, Eli G Cytrynbaum, Kevin A Macias, Sylvie E Oldeman, Kayla J Oliveira, Molly M Moore, Esmat Hegazi, Carmen Adriaens, Fadi J Najm, George D Demetri, Sonia Cohen, John T Mullen, Nicolò Riggi, Sarah E Johnstone, Bradley E Bernstein.

  Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.

Keywords:  MDM2; P53 independent; epigenetics; genome topology; liposarcoma; sarcoma; therapeutic resistance

DOI:  https://doi.org/10.1016/j.xgen.2023.100321
J Biol Chem. 2023 Jul 26. pii: S0021-9258(23)02131-2. [Epub ahead of print] 105103

Intracellular Energy Production and Distribution in Hypoxia.

Darragh Flood, Eun Sang Lee, Cormac Taylor.

The hydrolysis of adenosine triphosphate (ATP) is the primary source of metabolic energy for most eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels of ATP to fuel the active biological processes necessary to maintain homeostasis. However, mechanisms underpinning the distribution of ATP to subcellular microenvironments with high local demand remain poorly understood. Intracellular distribution of ATP in normal physiological conditions has been proposed to rely on passive diffusion across concentration gradients generated by ATP producing systems such as the mitochondria and the glycolytic pathway. However, subcellular microenvironments can develop with ATP deficiency due to increases in local ATP consumption. Alternatively, ATP production can be reduced during bioenergetic stress through exposure to hypoxia. Mammalian cells therefore need to have the capacity to alter their metabolism and energy distribution strategies to compensate for local ATP deficits while also controlling ATP production. It is highly likely that satisfying the bioenergetic requirements of the cell involves the regulated distribution of ATP producing systems to areas of high ATP demand within the cell. Recently, the distribution (both spatially and temporally) of ATP-producing systems has become an area of intense investigation. Here we review what is known (and unknown) about intracellular energy production and distribution and explore potential mechanisms through which this targeted distribution can be altered in hypoxia, with the aim of stimulating investigation in this important, yet poorly understood field of research.

DOI: https://doi.org/10.1016/j.jbc.2023.105103
bioRxiv. 2023 Jul 10. pii: 2023.07.10.548411. [Epub ahead of print]

3-hydroxykynurenine is a ROS-inducing cytotoxic tryptophan metabolite that disrupts the TCA cycle.

Jane L Buchanan, Adam J Rauckhorst, Eric B Taylor.

Tryptophan is an essential amino acid that is extensively characterized as a regulator of cellular function through its metabolism by indoleamine 2,3-deoxygenase (IDO) into the kynurenine pathway. However, despite decades of research on tryptophan metabolism, the metabolic regulatory roles of it and its metabolites are not well understood. To address this, we performed an activity metabolomics screen of tryptophan and most of its known metabolites in cell culture. We discovered that treatment of human colon cancer cells (HCT116) with 3-hydroxykynurenine (3-HK), a metabolite of kynurenine, potently disrupted TCA cycle function. Citrate and aconitate levels were increased, while isocitrate and all downstream TCA metabolites were decreased, suggesting decreased aconitase function. We hypothesized that 3HK or one of its metabolites increased reactive oxygen species (ROS) and inhibited aconitase activity. Accordingly, we observed almost complete depletion of reduced glutathione and a decrease in total glutathione levels. We observed a dose-dependent decrease in cell viability after 48 hours of 3HK treatment. These data suggest that raising the intracellular levels of 3HK could be sufficient to induce ROS-mediated apoptosis. We modulated the intracellular levels of 3HK by combined induction of IDO and knockdown of kynureninase (KYNU) in HCT116 cells. Cell viability decreased significantly after 48 hours of KYNU knockdown compared to controls, which was accompanied by increased ROS production and Annexin V staining revealing apoptosis. Finally, we identify xanthommatin production from 3-HK as a candidate radical-producing, cytotoxic mechanism. Our work indicates that KYNU may be a target for disrupting tryptophan metabolism. Interestingly, many cancers exhibit overexpression of IDO, providing a cancer-specific metabolic vulnerability that could be exploited by KYNU inhibition.

DOI: https://doi.org/10.1101/2023.07.10.548411
Cell Rep. 2023 Jul 25. pii: S2211-1247(23)00879-3. [Epub ahead of print]42(8): 112868

mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching.

Sejeong Shin, Min-Joon Han, Mark P Jedrychowski, Ziyang Zhang, Kevan M Shokat, David R Plas, Noah Dephoure, Sang-Oh Yoon.

  Cells maintain and dynamically change their proteomes according to the environment and their needs. Mechanistic target of rapamycin (mTOR) is a key regulator of proteostasis, homeostasis of the proteome. Thus, dysregulation of mTOR leads to changes in proteostasis and the consequent progression of diseases, including cancer. Based on the physiological and clinical importance of mTOR signaling, we investigated mTOR feedback signaling, proteostasis, and cell fate. Here, we reveal that mTOR targeting inhibits eIF4E-mediated cap-dependent translation, but feedback signaling activates a translation initiation factor, eukaryotic translation initiation factor 3D (eIF3D), to sustain alternative non-canonical translation mechanisms. Importantly, eIF3D-mediated protein synthesis enables cell phenotype switching from proliferative to more migratory. eIF3D cooperates with mRNA-binding proteins such as heterogeneous nuclear ribonucleoprotein F (hnRNPF), heterogeneous nuclear ribonucleoprotein K (hnRNPK), and Sjogren syndrome antigen B (SSB) to support selective mRNA translation following mTOR inhibition, which upregulates and activates proteins involved in insulin receptor (INSR)/insulin-like growth factor 1 receptor (IGF1R)/insulin receptor substrate (IRS) and interleukin 6 signal transducer (IL-6ST)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. Our study highlights the mechanisms by which cells establish the dynamic change of proteostasis and the resulting phenotype switch.

Keywords:  CP: Cell biology; CP: Molecular biology; eIF3D; eIF4E; mRNA translation; mTOR; proteome; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2023.112868
EMBO Rep. 2023 Jul 25. e56279

Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells.

Kevin M Rattigan, Martha M Zarou, Zuzana Brabcova, Bodhayan Prasad, Désirée Zerbst, Daniele Sarnello, Eric R Kalkman, Angela Ianniciello, Mary T Scott, Karen Dunn, Engy Shokry, David Sumpton, Mhairi Copland, Saverio Tardito, Johan Vande Voorde, Francis Mussai, Paul Cheng, G Vignir Helgason.

  To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient-derived CML CD34+ cells, rendering them arginine auxotrophic. Thus, arginine deprivation completely blocks proliferation of CML CD34+ cells and induces significantly higher levels of apoptosis when compared to arginine-deprived cell lines. Similarly, primary CML cells, but not normal CD34+ samples, are particularly sensitive to treatment with the arginine-depleting enzyme, BCT-100, which induces apoptosis and reduces clonogenicity. Moreover, BCT-100 is highly efficacious in a patient-derived xenograft model, causing > 90% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs.

Keywords:  amino acids; leukaemic stem cells; metabolism; therapy resistance

DOI:  https://doi.org/10.15252/embr.202256279
Elife. 2023 Jul 26. pii: e87705. [Epub ahead of print]12

Searching for molecular hypoxia sensors among oxygen-dependent enzymes.

Li Li, Susan Shen, Philip Bickler, Matthew P Jacobson, Lani F Wu, Steven J Altschuler.

  The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O2-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.

Keywords:  cell biology; hypoxia; hypoxia sensors; oxygen; oxygen-dependent enzymes

DOI:  https://doi.org/10.7554/eLife.87705
Cell Metab. 2023 Jul 18. pii: S1550-4131(23)00227-9. [Epub ahead of print]

Lactate modulates iron metabolism by binding soluble adenylyl cyclase.

Wei Liu, Shuping Zhang, Quanjin Li, Yue Wu, Xuan Jia, Wenya Feng, Zhaolong Li, Yali Shi, Qingzhi Hou, Juan Ma, Yajun Liu, Pu Gao, Tomas Ganz, Sijin Liu.

  Overproduction of lactate (LA) can occur during exercise and in many diseases such as cancers. Individuals with hyperlactatemia often display anemia, decreased serum iron, and elevated hepcidin, a key regulator of iron metabolism. However, it is unknown whether and how LA regulates hepcidin expression. Here, we show LA binds to soluble adenylyl cyclase (sAC) in normal hepatocytes and affects systemic iron homeostasis in mice by increasing hepcidin expression. Comprehensive in vitro, in vivo, and in silico experiments show that the LA-sAC interaction raises cyclic adenosine monophosphate (cAMP) levels, which activates the PKA-Smad1/5/8 signaling pathway to increase hepcidin transcription. We verified this regulatory axis in wild-type mice and in mice with disordered iron homeostasis. LA also regulates hepcidin in humans at rest and subjected to extensive exercise that produce elevated LA. Our study links hyperlactatemia to iron deficiency, offering a mechanistic explanation for anemias seen in athletes and patients with lactic acidosis.

Keywords:  hepcidin; iron metabolism; lactate; messenger molecule; sensor

DOI:  https://doi.org/10.1016/j.cmet.2023.06.017
Nat Rev Endocrinol. 2023 Jul 28.

Fetal orchestration of maternal metabolism via IGF2.

Shimona Starling.

DOI: https://doi.org/10.1038/s41574-023-00884-7
Cell Rep. 2023 Jul 16. pii: S2211-1247(23)00802-1. [Epub ahead of print] 112791

FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy.

CRUK IMAXT Grand Challenge Team

  Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics.

Keywords:  CP: Cancer; anti-angiogenic therapy; epithelial-to-endothelial transistion; transcriptional reprogramming; transdifferentiation; tumor vasculature

DOI:  https://doi.org/10.1016/j.celrep.2023.112791
Cell Discov. 2023 Jul 25. 9(1): 76

The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth.

Xiaojun Ren, Jimei Yan, Qiongya Zhao, Xinzhu Bao, Xinyu Han, Chen Zheng, Yan Zhou, Lifang Chen, Bo Wang, Lina Yang, Xi Lin, Dandan Liu, Yuyan Lin, Min Li, Hezhi Fang, Zhimin Lu, Jianxin Lyu.

IscU2 is a scaffold protein that is critical for the assembly of iron-sulfur (Fe-S) clusters and the functions of Fe-S-containing mitochondrial proteins. However, the role of IscU2 in tumor development remains unclear. Here, we demonstrated that IscU2 expression is much higher in human pancreatic ductal adenocarcinoma (PDAC) tissues than in adjacent normal pancreatic tissues. In PDAC cells, activated KRAS enhances the c-Myc-mediated IscU2 transcription. The upregulated IscU2 stabilizes Fe-S cluster and regulates the activity of tricarboxylic acid (TCA) cycle enzymes α-ketoglutarate (α-KG) dehydrogenase and aconitase 2, which promote α-KG catabolism through oxidative and reductive TCA cycling, respectively. In addition to promoting mitochondrial functions, activated KRAS-induced and IscU2-dependent acceleration of α-KG catabolism results in reduced α-KG levels in the cytosol and nucleus, leading to an increase in DNA 5mC due to Tet methylcytosine dioxygenase 3 (TET3) inhibition and subsequent expression of genes including DNA polymerase alpha 1 catalytic subunit for PDAC cell proliferation and tumor growth in mice. These findings underscore a critical role of IscU2 in KRAS-promoted α-KG catabolism, 5mC-dependent gene expression, and PDAC growth and highlight the instrumental and integrated regulation of mitochondrial functions and gene expression by IscU2 in PDAC cells.

DOI: https://doi.org/10.1038/s41421-023-00558-8
Cell Rep. 2023 Jul 26. pii: S2211-1247(23)00906-3. [Epub ahead of print]42(8): 112895

PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics.

Sudeshna Nag, Kaitlin Szederkenyi, Olena Gorbenko, Hannah Tyrrell, Christopher M Yip, G Angus McQuibban.

  Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein 1 (DRP1). Mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is emerging as a regulator of these post-translational modifications; however, its precise role in the regulation of mitochondrial morphology is unknown. We show that PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner. PGAM5 regulates MFN2 phosphorylation and consequently protects it from ubiquitination and degradation. Further, phosphorylation and dephosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances fission and degradation, whereas dephosphorylation enhances fusion. PGAM5 dephosphorylates MFN2 to promote mitochondrial network formation. Further, using a Drosophila genetic model, we demonstrate that the MFN2 homolog Marf and dPGAM5 are in the same biological pathway. Our results identify MFN2 dephosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase.

Keywords:  CP: Molecular biology; DRP1; MFN2; PGAM5; mitochondrial morphology

DOI:  https://doi.org/10.1016/j.celrep.2023.112895
Nat Aging. 2023 Jul 24.

Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement.

Hye-Sook Han, Eunyong Ahn, Eun Seo Park, Tom Huh, Seri Choi, Yongmin Kwon, Byeong Hun Choi, Jueun Lee, Yoon Ha Choi, Yujin L Jeong, Gwang Bin Lee, Minji Kim, Je Kyung Seong, Hyun Mu Shin, Hang-Rae Kim, Myeong Hee Moon, Jong Kyoung Kim, Geum-Sook Hwang, Seung-Hoi Koo.

Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo.

DOI: https://doi.org/10.1038/s43587-023-00460-8
Life Sci Alliance. 2023 10;pii: e202201886. [Epub ahead of print]6(10):

Reciprocal regulation between the molecular clock and kidney injury.

Carlos Rey-Serra, Jessica Tituaña, Terry Lin, J Ignacio Herrero, Verónica Miguel, Coral Barbas, Anna Meseguer, Ricardo Ramos, Amandine Chaix, Satchidananda Panda, Santiago Lamas.

Tubulointerstitial fibrosis is the common pathological substrate for many etiologies leading to chronic kidney disease. Although perturbations in the circadian rhythm have been associated with renal disease, the role of the molecular clock in the pathogenesis of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (unilateral ureteral obstruction, folic acid, and adenine nephrotoxicity), using genetically modified mice with selective deficiencies of the clock components Bmal1, Clock, and Cry We found that the molecular clock pathway was enriched in damaged tubular epithelial cells with marked metabolic alterations. In human tubular epithelial cells, TGFβ significantly altered the expression of clock components. Although Clock played a role in the macrophage-mediated inflammatory response, the combined absence of Cry1 and Cry2 was critical for the recruitment of neutrophils, correlating with a worsening of fibrosis and with a major shift in the expression of metabolism-related genes. These results support that renal damage disrupts the kidney peripheral molecular clock, which in turn promotes metabolic derangement linked to inflammatory and fibrotic responses.

DOI: https://doi.org/10.26508/lsa.202201886
Nat Cell Biol. 2023 Jul 24.

The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates.

Yihao Yang, Nicholas Gomez, Nicole Infarinato, Rene C Adam, Megan Sribour, Inwha Baek, Mélanie Laurin, Elaine Fuchs.

During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.

DOI: https://doi.org/10.1038/s41556-023-01184-y
Nat Rev Cancer. 2023 Jul 24.

Cancers make their own luck: theories of cancer origins.

Amir Jassim, Eric P Rahrmann, Ben D Simons, Richard J Gilbertson.

Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is 'bad luck': the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues 'walk a tightrope', retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as 'bad luck', understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable.

DOI: https://doi.org/10.1038/s41568-023-00602-5
Cell Metab. 2023 Jul 21. pii: S1550-4131(23)00251-6. [Epub ahead of print]

Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.

Lijian Wu, Yiteng Jin, Xi Zhao, Kaiyang Tang, Yaoning Zhao, Linjie Tong, Xuerong Yu, Ke Xiong, Ce Luo, Jiajun Zhu, Fubing Wang, Zexian Zeng, Deng Pan.

  Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically, Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, which generates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiate tumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- and Fadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-α pathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-induced killing provides new therapeutic strategies to enhance anti-tumor immunity.

Keywords:  T cell-mediated killing; TNF-α; glycolysis; immune evasion

DOI:  https://doi.org/10.1016/j.cmet.2023.07.001
Phys Rev Lett. 2023 Jul 14. 131(2): 028401

Linear Response Theory of Evolved Metabolic Systems.

Jumpei F Yamagishi, Tetsuhiro S Hatakeyama.

Predicting cellular metabolic states is a central problem in biophysics. Conventional approaches, however, sensitively depend on the microscopic details of individual metabolic systems. In this Letter, we derived a universal linear relationship between the metabolic responses against nutrient conditions and metabolic inhibition, with the aid of a microeconomic theory. The relationship holds in arbitrary metabolic systems as long as the law of mass conservation stands, as supported by extensive numerical calculations. It offers quantitative predictions without prior knowledge of systems.

DOI: https://doi.org/10.1103/PhysRevLett.131.028401
Nature. 2023 Jul 26.

Rewiring cancer drivers to activate apoptosis.

Sai Gourisankar, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H Kim, Zhengnian Li, Wendy Wenderski, Juste M Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R Green, Nathanael S Gray, Gerald R Crabtree.

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.

DOI: https://doi.org/10.1038/s41586-023-06348-2
J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2023 Jul 23.

On the origin and evolution of the dual oscillator model underlying the photoperiodic clockwork in the suprachiasmatic nucleus.

Jennifer A Evans, William J Schwartz.

  Decades have now passed since Colin Pittendrigh first proposed a model of a circadian clock composed of two coupled oscillators, individually responsive to the rising and setting sun, as a flexible solution to the challenge of behavioral and physiological adaptation to the changing seasons. The elegance and predictive power of this postulation has stimulated laboratories around the world in searches to identify and localize such hypothesized evening and morning oscillators, or sets of oscillators, in insects, rodents, and humans, with experimental designs and approaches keeping pace over the years with technological advances in biology and neuroscience. Here, we recount the conceptual origin and highlight the subsequent evolution of this dual oscillator model for the circadian clock in the mammalian suprachiasmatic nucleus; and how, despite our increasingly sophisticated view of this multicellular pacemaker, Pittendrigh's binary conception has remained influential in our clock models and metaphors.

Keywords:  Circadian; Complex clock; Coupled oscillators; Evening; Morning; Photoperiod; SCN

DOI:  https://doi.org/10.1007/s00359-023-01659-1
Proc Natl Acad Sci U S A. 2023 08;120(31): e2300475120

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.

Qingqing Liu, Benjamin Fong, Seungmin Yoo, Jay R Unruh, Fengli Guo, Zulin Yu, Jingjing Chen, Kausik Si, Rong Li, Chuankai Zhou.

  Eukaryotes organize cellular contents into membrane-bound organelles and membrane-less condensates, for example, protein aggregates. An unsolved question is why the ubiquitously distributed proteins throughout the cytosol give rise to spatially localized protein aggregates on the organellar surface, like mitochondria. We report that the mitochondrial import receptor Tom70 is involved in the localized condensation of protein aggregates in budding yeast and human cells. This is because misfolded cytosolic proteins do not autonomously aggregate in vivo; instead, they are recruited to the condensation sites initiated by Tom70's substrates (nascent mitochondrial proteins) on the organellar membrane using multivalent hydrophobic interactions. Knocking out Tom70 partially impairs, while overexpressing Tom70 increases the formation and association between cytosolic protein aggregates and mitochondria. In addition, ectopic targeting Tom70 and its substrates to the vacuole surface is able to redirect the localized aggregation from mitochondria to the vacuolar surface. Although other redundant mechanisms may exist, this nascent mitochondrial proteins-based initiation of protein aggregation likely explains the localized condensation of otherwise ubiquitously distributed molecules on the mitochondria. Disrupting the mitochondrial association of aggregates impairs their asymmetric retention during mitosis and reduces the mitochondrial import of misfolded proteins, suggesting a proteostasis role of the organelle-condensate interactions.

Keywords:  condensate; mitochondria; protein aggregation

DOI:  https://doi.org/10.1073/pnas.2300475120
Elife. 2023 Jul 28. pii: e84710. [Epub ahead of print]12

Mitochondrial defects leading to arrested spermatogenesis and ferroptosis in the PARL deficient mouse model of Leigh Syndrome.

Enrico Radaelli, Charles-Antoine Assenmacher, Jillian Verrelle, Esha Banerjee, Florence Manero, Salim Khiati, Anais Girona, Guillermo Lopez-Lluch, Placido Navas, Marco Spinazzi.

  Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis at meiotic prophase I, followed by germ cell death independently of neurodegeneration. Genetic modifications of PINK1, PGAM5, and TTC19, three major substrates of PARL with important roles in mitochondrial homeostasis, do not reproduce or modify this severe phenotype. PARL deficiency in spermatocytes leads to severe abnormalities in mitochondrial structure associated with prominent electron transfer chain defects, alterations in Coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ-cell specific decrease in GPX4 expression committing arrested spermatocytes to ferroptosis, a regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects, such as those induced by depletion of PARL, spontaneously initiate ferroptosis in primary spermatocytes in vivo by simultaneous effects on GPX4 and CoQ, the two major ferroptosis-inhibitors. Ferroptosis warrants to be further scrutinized in the pathogenesis of mitochondrial diseases and male infertility.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.84710
bioRxiv. 2023 Jul 19. pii: 2023.07.19.549715. [Epub ahead of print]

A Cell Cycle-Dependent Ferroptosis Sensitivity Switch Governed by EMP2.

Jason Rodencal, Nathan Kim, Veronica L Li, Andrew He, Mike Lange, Jianping He, Amy Tarangelo, Zachary T Schafer, James A Olzmann, Julien Sage, Jonathan Z Long, Scott J Dixon.

Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. Ferroptosis can be induced by system x c - cystine/glutamate antiporter inhibition or by direct inhibition of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). The regulation of ferroptosis in response to system x c - inhibition versus direct GPX4 inhibition may be distinct. Here, we show that cell cycle arrest enhances sensitivity to ferroptosis triggered by GPX4 inhibition but not system x c - inhibition. Arrested cells have increased levels of oxidizable polyunsaturated fatty acid-containing phospholipids, which drives sensitivity to GPX4 inhibition. Epithelial membrane protein 2 (EMP2) expression is reduced upon cell cycle arrest and is sufficient to enhance ferroptosis in response to direct GPX4 inhibition. An orally bioavailable GPX4 inhibitor increased markers of ferroptotic lipid peroxidation in vivo in combination with a cell cycle arresting agent. Thus, responses to different ferroptosis-inducing stimuli can be regulated by cell cycle state.

DOI: https://doi.org/10.1101/2023.07.19.549715
Antioxidants (Basel). 2023 Jul 21. pii: 1469. [Epub ahead of print]12(7):

Biosynthesis, Deficiency, and Supplementation of Coenzyme Q.

Carmine Staiano, Laura García-Corzo, David Mantle, Nadia Turton, Lauren E Millichap, Gloria Brea-Calvo, Iain Hargreaves.

  Originally identified as a key component of the mitochondrial respiratory chain, Coenzyme Q (CoQ or CoQ10 for human tissues) has recently been revealed to be essential for many different redox processes, not only in the mitochondria, but elsewhere within other cellular membrane types. Cells rely on endogenous CoQ biosynthesis, and defects in this still-not-completely understood pathway result in primary CoQ deficiencies, a group of conditions biochemically characterised by decreased tissue CoQ levels, which in turn are linked to functional defects. Secondary CoQ deficiencies may result from a wide variety of cellular dysfunctions not directly linked to primary synthesis. In this article, we review the current knowledge on CoQ biosynthesis, the defects leading to diminished CoQ10 levels in human tissues and their associated clinical manifestations.

Keywords:  CoQ biosynthesis; CoQ deficiency; Coenzyme Q; blood-brain barrier; statins

DOI:  https://doi.org/10.3390/antiox12071469
Nat Metab. 2023 Jul;5(7): 1088-1100

Interleukin-17 as a key player in neuroimmunometabolism.

Aaron Douglas, Brenneth Stevens, Lydia Lynch.

In mammals, interleukin (IL)-17 cytokines are produced by innate and adaptive lymphocytes. However, the IL-17 family has widespread expression throughout evolution, dating as far back as cnidaria, molluscs and worms, which predate lymphocytes. The evolutionary conservation of IL-17 suggests that it is involved in innate defence strategies, but also that this cytokine family has a fundamental role beyond typical host defence. Throughout evolution, IL-17 seems to have a major function in homeostatic maintenance at barrier sites. Most recently, a pivotal role has been identified for IL-17 in regulating cellular metabolism, neuroimmunology and tissue physiology, particularly in adipose tissue. Here we review the emerging role of IL-17 signalling in regulating metabolic processes, which may shine a light on the evolutionary role of IL-17 beyond typical immune responses. We propose that IL-17 helps to coordinate the cross-talk among the nervous, endocrine and immune systems for whole-body energy homeostasis as a key player in neuroimmunometabolism.

DOI: https://doi.org/10.1038/s42255-023-00846-3
EMBO Mol Med. 2023 Jul 25. e16858

Platelet-derived lipids promote insulin secretion of pancreatic β cells.

Till Karwen, Katarzyna Kolczynska-Matysiak, Carina Gross, Mona C Löffler, Mike Friedrich, Angel Loza-Valdes, Werner Schmitz, Magdalena Wit, Filip Dziaczkowski, Andrei Belykh, Jonathan Trujillo-Viera, Rabih El-Merahbi, Carsten Deppermann, Sameena Nawaz, Benoit Hastoy, Agnieszka Demczuk, Manuela Erk, Mariusz R Wieckowski, Patrik Rorsman, Katrin G Heinze, David Stegner, Bernhard Nieswandt, Grzegorz Sumara.

  Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic β cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from β cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting β cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on β cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.

Keywords:  20-HETE; diabetes; insulin secretion; platelet; β cell

DOI:  https://doi.org/10.15252/emmm.202216858
Sci Adv. 2023 Jul 28. 9(30): eadg2829

Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.

Kristel Martinez Lagunas, Deniz Pinar Savcigil, Matea Zrilic, Carlos Carvajal Fraile, Andrew Craxton, Emily Self, Iratxe Uranga-Murillo, Diego de Miguel, Maykel Arias, Sebastian Willenborg, Michael Piekarek, Marie Christine Albert, Kalvin Nugraha, Ina Lisewski, Erika Janakova, Natalia Igual, Wulf Tonnus, Ximena Hildebrandt, Mohammed Ibrahim, Marlies Ballegeer, Xavier Saelens, Andrew Kueh, Pascal Meier, Andreas Linkermann, Julian Pardo, Sabine Eming, Henning Walczak, Marion MacFarlane, Nieves Peltzer, Alessandro Annibaldi.

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, CflipD377A, exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)-induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs.

DOI: https://doi.org/10.1126/sciadv.adg2829
Nat Cancer. 2023 07;4(7): 955-967

Leveraging translational insights toward precision medicine approaches for brain metastases.

Albert E Kim, Edwin Nieblas-Bedolla, Magali A de Sauvage, Priscilla K Brastianos.

Due to increasing incidence and limited treatments, brain metastases (BM) are an emerging unmet need in modern oncology. Development of effective therapeutics has been hindered by unique challenges. Individual steps of the brain metastatic cascade are driven by distinctive biological processes, suggesting that BM possess intrinsic biological differences compared to primary tumors. Here, we discuss the unique physiology and metabolic constraints specific to BM as well as emerging treatment strategies that leverage potential vulnerabilities.

DOI: https://doi.org/10.1038/s43018-023-00585-0
Nature. 2023 Jul 26.

Evolutionary histories of breast cancer and related clones.

Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Takaki Sakurai, Tatsuki R Kataoka, Eiji Kondoh, Yoshitsugu Chigusa, Masahiko Kawai, Morio Sawada, Takuya Inoue, Yasuhide Takeuchi, Hirona Maeda, Satoko Baba, Yusuke Shiozawa, Ryunosuke Saiki, Masahiro M Nakagawa, Yasuhito Nannya, Yotaro Ochi, Tomonori Hirano, Tomoe Nakagawa, Yukiko Inagaki-Kawata, Kosuke Aoki, Masahiro Hirata, Kosaku Nanki, Mami Matano, Megumu Saito, Eiji Suzuki, Masahiro Takada, Masahiro Kawashima, Kosuke Kawaguchi, Kenichi Chiba, Yuichi Shiraishi, Junko Takita, Satoru Miyano, Masaki Mandai, Toshiro Sato, Kengo Takeuchi, Hironori Haga, Masakazu Toi, Seishi Ogawa.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

DOI: https://doi.org/10.1038/s41586-023-06333-9
Sci Adv. 2023 Jul 28. 9(30): eadg1805

Control of protein synthesis through mRNA pseudouridylation by dyskerin.

Chiara Pederiva, Davide M Trevisan, Dimitra Peirasmaki, Shan Chen, Sharon A Savage, Ola Larsson, Jernej Ule, Laura Baranello, Federico Agostini, Marianne Farnebo.

Posttranscriptional modifications of mRNA have emerged as regulators of gene expression. Although pseudouridylation is the most abundant, its biological role remains poorly understood. Here, we demonstrate that the pseudouridine synthase dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a guide RNA with full complementarity. In cells lacking dyskerin, mRNA pseudouridylation is reduced, while at the same time, de novo protein synthesis is enhanced, indicating that this modification interferes with translation. Accordingly, mRNAs with fewer pseudouridines due to knockdown of dyskerin are translated more efficiently. Moreover, mRNA pseudouridylation is severely reduced in patients with dyskeratosis congenita caused by inherited mutations in the gene encoding dyskerin (i.e., DKC1). Our findings demonstrate that pseudouridylation by dyskerin modulates mRNA translatability, with important implications for both normal development and disease.

DOI: https://doi.org/10.1126/sciadv.adg1805
Nat Chem Biol. 2023 Jul 27.

ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism.

Linchong Sun, Caixia Suo, Tong Zhang, Shengqi Shen, Xuemei Gu, Shiqiao Qiu, Pinggen Zhang, Haoran Wei, Wenhao Ma, Ronghui Yan, Rui Chen, Weidong Jia, Jie Cao, Huafeng Zhang, Ping Gao.

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.

DOI: https://doi.org/10.1038/s41589-023-01391-6