bims-camemi 2023-05-14 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023–05–14
27 papers selected by
Christian Frezza, Universität zu Köln

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.
A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis.
Assembly of the Mitochondrial Translation Initiation Complex.
Newly imported proteins in mitochondria are particularly sensitive to aggregation.
Mitochondrial Ion Channels.
Zebrafish imaging reveals hidden oncogenic-normal cell communication during primary tumorigenesis.
Optimization of energy production and central carbon metabolism in a non-respiring eukaryote.
Fuel oxidation under the control of mitochondrial shape and dynamics.
The REV-ERB Nuclear Receptors: Timekeepers for the core clock period and metabolism.
Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy.
Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.
The role of efferocytosis-fueled macrophage metabolism in the resolution of inflammation.
Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma.
S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling.
Circadian clock protein BMAL1 broadly influences autophagy and endolysosomal function in astrocytes.
Mitotic clustering of pulverized chromosomes from micronuclei.
The PLOD2/succinate axis regulates the epithelial-mesenchymal plasticity and cancer cell stemness.
Human metabolome variation along the upper intestinal tract.
Immune mechanisms shape the clonal landscape during early progression of prostate cancer.
MTHFD2 reprograms macrophage polarization by inhibiting PTEN.
Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function.
A prime editor mouse to model a broad spectrum of somatic mutations in vivo.
Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells.
Insights into mitoribosomal biogenesis from recent structural studies.
A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression.
Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.
Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota.

Cell Rep. 2023 May 08. pii: S2211-1247(23)00499-0. [Epub ahead of print]42(5): 112488

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.

Adilson Guilherme, Leslie A Rowland, Nicole Wetoska, Emmanouela Tsagkaraki, Kaltinaitis B Santos, Alexander H Bedard, Felipe Henriques, Mark Kelly, Sean Munroe, David J Pedersen, Olga R Ilkayeva, Timothy R Koves, Lauren Tauer, Meixia Pan, Xianlin Han, Jason K Kim, Christopher B Newgard, Deborah M Muoio, Michael P Czech.

  Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA.

Keywords:  ACC1; CP: Metabolism; FASN; UCP1; acetyl-CoA; adipose tissue; browning; fatty acids; lipogenesis; malonyl-CoA; thermogenesis

DOI:  https://doi.org/10.1016/j.celrep.2023.112488
J Cell Biol. 2023 Jul 03. pii: e202210019. [Epub ahead of print]222(7):

A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis.

Esra Peker, Konstantin Weiss, Jiyao Song, Christine Zarges, Sarah Gerlich, Volker Boehm, Aleksandra Trifunovic, Thomas Langer, Niels H Gehring, Thomas Becker, Jan Riemer.

Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway linking IMS and matrix import systems. A weak targeting sequence drives TIM23-dependent NDUFAF8 matrix import, and en route, allows exposure to the IMS disulfide relay, which oxidizes NDUFAF8. Import is closely surveyed by proteases: YME1L prevents accumulation of excess NDUFAF8 in the IMS, while CLPP degrades reduced NDUFAF8 in the matrix. Therefore, NDUFAF8 can only fulfil its function in complex I biogenesis if both oxidation in the IMS and subsequent matrix import work efficiently. We propose that the two-step import pathway for NDUFAF8 allows integration of the activity of matrix complex I biogenesis pathways with the activity of the mitochondrial disulfide relay system in the IMS. Such coordination might not be limited to NDUFAF8 as we identified further proteins that can follow such a two-step import pathway.

DOI: https://doi.org/10.1083/jcb.202210019
Methods Mol Biol. 2023 ;2661 217-232

Assembly of the Mitochondrial Translation Initiation Complex.

Cristina Remes, Minh Duc Nguyen, Henrik Spahr, Martin Ng, Clark Fritsch, Arpan Bhattacharya, Hong Li, Barry Cooperman, Joanna Rorbach.

  Mitochondria maintain their own translational machinery that is responsible for the synthesis of essential components of the oxidative phosphorylation system. The mammalian mitochondrial translation system differs significantly from its cytosolic and bacterial counterparts. Here, we describe detailed protocols for efficient in vitro reconstitution of the mammalian mitochondrial translation initiation complex, which can be further used for mechanistic analyses of different aspects of mitochondrial translation.

Keywords:  Mitoribosome; Translation; Translation factors; Translation initiation; tRNA purification

DOI:  https://doi.org/10.1007/978-1-0716-3171-3_13
Acta Physiol (Oxf). 2023 May 12. e13985

Newly imported proteins in mitochondria are particularly sensitive to aggregation.

Carmela Vazquez-Calvo, Verena Kohler, Johanna L Höög, Sabrina Büttner, Martin Ott.

   AIM: A functional proteome is essential for life and maintained by protein quality control (PQC) systems in the cytosol and organelles. Protein aggregation is an indicator of a decline of PQC linked to aging and disease. Mitochondrial PQC is critical to maintain mitochondrial function and thus cellular fitness. How mitochondria handle aggregated proteins is not well understood. Here we tested how the metabolic status impacts on formation and clearance of aggregates within yeast mitochondria and assessed which proteins are particularly sensitive to denaturation.
METHODS: Confocal microscopy, electron microscopy, immunoblotting and genetics were applied to assess mitochondrial aggregate handling in response to heat shock and ethanol, using the mitochondrial disaggregase Hsp78 as a marker for protein aggregates.
RESULTS: We show that aggregates formed upon heat or ethanol stress with different dynamics depending on the metabolic state. While fermenting cells displayed numerous small aggregates that coalesced into one large foci that was resistant to clearance, respiring cells showed less aggregates and cleared these aggregates more efficiently. Acute inhibition of mitochondrial translation had no effect, while preventing protein import into mitochondria by inhibition of cytosolic translation prevented aggregate formation.
CONCLUSION: Collectively, our data show that the metabolic state of the cells impacts the dynamics of aggregate formation and clearance, and that mainly newly imported and not yet assembled proteins are prone to form aggregates. Because mitochondrial functionality is crucial for cellular metabolism, these results highlight the importance of efficient protein biogenesis to maintain the mitochondrial proteome operational during metabolic adaptations and cellular stress.

Keywords:  Ageing; Aggregates; Cellular stress; Hsp78; Metabolism; Mitochondria; Protein quality control; Proteostasis

DOI:  https://doi.org/10.1111/apha.13985
Annu Rev Biophys. 2023 05 09. 52 229-254

Mitochondrial Ion Channels.

Ildiko Szabo, Adam Szewczyk.

  Mitochondria are involved in multiple cellular tasks, such as ATP synthesis, metabolism, metabolite and ion transport, regulation of apoptosis, inflammation, signaling, and inheritance of mitochondrial DNA. The majority of the correct functioning of mitochondria is based on the large electrochemical proton gradient, whose component, the inner mitochondrial membrane potential, is strictly controlled by ion transport through mitochondrial membranes. Consequently, mitochondrial function is critically dependent on ion homeostasis, the disturbance of which leads to abnormal cell functions. Therefore, the discovery of mitochondrial ion channels influencing ion permeability through the membrane has defined a new dimension of the function of ion channels in different cell types, mainly linked to the important tasks that mitochondrial ion channels perform in cell life and death. This review summarizes studies on animal mitochondrial ion channels with special focus on their biophysical properties, molecular identity, and regulation. Additionally, the potential of mitochondrial ion channels as therapeutic targets for several diseases is briefly discussed.

Keywords:  calcium channels; chloride channels; mitochondria; mitochondrial megachannel; porin; potassium channels

DOI:  https://doi.org/10.1146/annurev-biophys-092622-094853
Cell Struct Funct. 2023 May 11.

Zebrafish imaging reveals hidden oncogenic-normal cell communication during primary tumorigenesis.

Yukinari Haraoka, Mai Miyake, Tohru Ishitani.

  Oncogenic mutations drive tumorigenesis, and single cells with oncogenic mutations act as the tumor seeds that gradually evolve into fully transformed tumors. However, oncogenic cell behavior and communication with neighboring cells during primary tumorigenesis remain poorly understood. We used the zebrafish, a small vertebrate model suitable for in vivo cell biology, to address these issues. We describe the cooperative and competitive communication between oncogenic cells and neighboring cells, as revealed by our recent zebrafish imaging studies. Newly generated oncogenic cells are actively eliminated by neighboring cells in healthy epithelia, whereas oncogenic cells cooperate with their neighbors to prime tumorigenesis in unhealthy epithelia via additional mutations or inflammation. In addition, we discuss the potential of zebrafish in vivo imaging to determine the initial steps of human tumorigenesis.Key words: zebrafish, imaging, cell-cell communication, cell competition, EDAC, senescence, primary tumorigenesis.

Keywords:  EDAC; cell competition; cell-cell communication; imaging; primary tumorigenesis; senescence; zebrafish

DOI:  https://doi.org/10.1247/csf.23026
Curr Biol. 2023 Apr 30. pii: S0960-9822(23)00528-6. [Epub ahead of print]

Optimization of energy production and central carbon metabolism in a non-respiring eukaryote.

Sara Alam, Ying Gu, Polina Reichert, Jürg Bähler, Snezhana Oliferenko.

  Most eukaryotes respire oxygen, using it to generate biomass and energy. However, a few organisms have lost the capacity to respire. Understanding how they manage biomass and energy production may illuminate the critical points at which respiration feeds into central carbon metabolism and explain possible routes to its optimization. Here, we use two related fission yeasts, Schizosaccharomyces pombe and Schizosaccharomyces japonicus, as a comparative model system. We show that although S. japonicus does not respire oxygen, unlike S. pombe, it is capable of efficient NADH oxidation, amino acid synthesis, and ATP generation. We probe possible optimization strategies through the use of stable isotope tracing metabolomics, mass isotopologue distribution analysis, genetics, and physiological experiments. S. japonicus appears to have optimized cytosolic NADH oxidation via glycerol-3-phosphate synthesis. It runs a fully bifurcated TCA pathway, sustaining amino acid production. Finally, we propose that it has optimized glycolysis to maintain high ATP/ADP ratio, in part by using the pentose phosphate pathway as a glycolytic shunt, reducing allosteric inhibition of glycolysis and supporting biomass generation. By comparing two related organisms with vastly different metabolic strategies, our work highlights the versatility and plasticity of central carbon metabolism in eukaryotes, illuminating critical adaptations supporting the preferential use of glycolysis over oxidative phosphorylation.

Keywords:  Schizosaccharomyces japonicus; Schizosaccharomyces pombe; TCA Cycle; bifurcated TCA pathway; fermentation; glycolysis; metabolomics; respiration

DOI:  https://doi.org/10.1016/j.cub.2023.04.046
EMBO J. 2023 May 08. e114129

Fuel oxidation under the control of mitochondrial shape and dynamics.

Erin L Seifert, György Hajnóczky.

How mitochondrial shape and substrate-specific metabolism are related has been a difficult question to address. Here, new work by Ngo et al (2023) reports that mitochondrial shape-long versus fragmented-determines the activity of β-oxidation of long-chain fatty acids, supporting a novel role for mitochondrial fission products as β-oxidation hubs.

DOI: https://doi.org/10.15252/embj.2023114129
Endocrinology. 2023 May 07. pii: bqad069. [Epub ahead of print]

The REV-ERB Nuclear Receptors: Timekeepers for the core clock period and metabolism.

Marine Adlanmerini, Mitchell A Lazar.

  REV-ERB nuclear receptors are potent transcriptional repressors that play an important role in the core mammalian molecular clock and metabolism. Deletion of both REV-ERBα and its largely redundant isoform REV-ERBβ in a murine tissue-specific manner have shed light on their specific functions in clock mechanisms and circadian metabolism. This review highlights recent findings that establish REV-ERBs as crucial circadian timekeepers in a variety of tissues, regulating overlapping and distinct processes that maintain normal physiology and protect from metabolic dysfunction.

Keywords:  Circadian rhythms; Desynchrony; Lipids; Metabolism; Molecular Clocks; Nuclear Receptors; REV-ERB

DOI:  https://doi.org/10.1210/endocr/bqad069
Elife. 2023 May 11. pii: e84280. [Epub ahead of print]12

Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy.

Pedro P Cunha, Eleanor Minogue, Lena C M Krause, Rita M Hess, David Bargiela, Brennan J Wadsworth, Laura Barbieri, Carolin Brombach, Iosifina P Foskolou, Ivan Bogeski, Pedro Velica, Randall S Johnson.

  Oxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hours of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.

Keywords:  human; immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.84280
Science. 2023 May 12. 380(6645): eadd5327

Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.

Cassandra Burdziak, Direna Alonso-Curbelo, Thomas Walle, José Reyes, Francisco M Barriga, Doron Haviv, Yubin Xie, Zhen Zhao, Chujun Julia Zhao, Hsuan-An Chen, Ojasvi Chaudhary, Ignas Masilionis, Zi-Ning Choo, Vianne Gao, Wei Luan, Alexandra Wuest, Yu-Jui Ho, Yuhong Wei, Daniela F Quail, Richard Koche, Linas Mazutis, Ronan Chaligné, Tal Nawy, Scott W Lowe, Dana Pe'er.

The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci. Using an inference approach, we revealed signaling gene modules and tissue-level cross-talk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that was functionally validated in mice. Our results uncover a neoplasia-specific tissue-remodeling program that may be exploited for pancreatic cancer interception.

DOI: https://doi.org/10.1126/science.add5327
Immunol Rev. 2023 May 09.

The role of efferocytosis-fueled macrophage metabolism in the resolution of inflammation.

Maaike Schilperoort, David Ngai, Santosh R Sukka, Kleopatra Avrampou, Hongxue Shi, Ira Tabas.

  The phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro-resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro-resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re-programming. Here, we review efferocytosis-induced changes in macrophage metabolism that mediate the pro-resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis-fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.

Keywords:  cell metabolism; efferocytosis; inflammation resolution; macrophages

DOI:  https://doi.org/10.1111/imr.13214
EMBO Mol Med. 2023 May 09. e16910

Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma.

Giulio Donati, Paola Nicoli, Alessandro Verrecchia, Veronica Vallelonga, Ottavio Croci, Simona Rodighiero, Matteo Audano, Laura Cassina, Aya Ghsein, Giorgio Binelli, Alessandra Boletta, Nico Mitro, Bruno Amati.

  MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS-010759. In a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro-oxidant at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.

Keywords:  MYC; ROS; lymphoma; mitochondria; targeted therapy

DOI:  https://doi.org/10.15252/emmm.202216910
Proc Natl Acad Sci U S A. 2023 05 16. 120(20): e2300763120

S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling.

Yeonjin Ko, Mannkyu Hong, Seungbeom Lee, Manoj Kumar, Lara Ibrahim, Kayla Nutsch, Caroline Stanton, Phillip Sondermann, Braddock Sandoval, Maya L Bulos, Jonathan Iaconelli, Arnab K Chatterjee, R Luke Wiseman, Peter G Schultz, Michael J Bollong.

  KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.

Keywords:  glycolysis; intrinsically reactive metabolite; posttranslational modification; pyruvate kinase

DOI:  https://doi.org/10.1073/pnas.2300763120
Proc Natl Acad Sci U S A. 2023 05 16. 120(20): e2220551120

Circadian clock protein BMAL1 broadly influences autophagy and endolysosomal function in astrocytes.

Celia A McKee, Alexander J Polino, Melvin W King, Erik S Musiek.

  An emerging role for the circadian clock in autophagy and lysosome function has opened new avenues for exploration in the field of neurodegeneration. The daily rhythms of circadian clock proteins may coordinate gene expression programs involved not only in daily rhythms but in many cellular processes. In the brain, astrocytes are critical for sensing and responding to extracellular cues to support neurons. The core clock protein BMAL1 serves as the primary positive circadian transcriptional regulator and its depletion in astrocytes not only disrupts circadian function but also leads to a unique cell-autonomous activation phenotype. We report here that astrocyte-specific deletion of Bmal1 influences endolysosome function, autophagy, and protein degradation dynamics. In vitro, Bmal1-deficient astrocytes exhibit increased endocytosis, lysosome-dependent protein cleavage, and accumulation of LAMP1- and RAB7-positive organelles. In vivo, astrocyte-specific Bmal1 knockout (aKO) brains show accumulation of autophagosome-like structures within astrocytes by electron microscopy. Transcriptional analysis of isolated astrocytes from young and aged Bmal1 aKO mice indicates broad dysregulation of pathways involved in lysosome function which occur independently of TFEB activation. Since a clear link has been established between neurodegeneration and endolysosome dysfunction over the course of aging, this work implicates BMAL1 as a key regulator of these crucial astrocyte functions in health and disease.

Keywords:  Bmal1; astrocyte; autophagy; circadian; lysosome

DOI:  https://doi.org/10.1073/pnas.2220551120
Nature. 2023 May 10.

Mitotic clustering of pulverized chromosomes from micronuclei.

Yu-Fen Lin, Qing Hu, Alice Mazzagatti, Jose Espejo Valle-Inclán, Elizabeth G Maurais, Rashmi Dahiya, Alison Guyer, Jacob T Sanders, Justin L Engel, Giaochau Nguyen, Daniel Bronder, Samuel F Bakhoum, Isidro Cortés-Ciriano, Peter Ly.

Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis1-5. As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis6. Here we tracked micronucleated chromosomes with live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for asymmetric inheritance by a single daughter cell. Mechanistically, the CIP2A-TOPBP1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises pulverized chromosomes for clustering upon mitotic entry. Inactivation of CIP2A-TOPBP1 caused acentric fragments to disperse throughout the mitotic cytoplasm, stochastically partition into the nucleus of both daughter cells and aberrantly misaccumulate as cytoplasmic DNA. Mitotic clustering facilitates the reassembly of acentric fragments into rearranged chromosomes lacking the extensive DNA copy-number losses that are characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer genomes revealed clusters of DNA copy-number-neutral rearrangements-termed balanced chromothripsis-across diverse tumour types resulting in the acquisition of known cancer driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial clustering of pulverized chromosomes from micronuclei.

DOI: https://doi.org/10.1038/s41586-023-05974-0
Proc Natl Acad Sci U S A. 2023 05 16. 120(20): e2214942120

The PLOD2/succinate axis regulates the epithelial-mesenchymal plasticity and cancer cell stemness.

Yuxin Tong, Yifei Qi, Gaofeng Xiong, Junyan Li, Timothy L Scott, Jie Chen, Daheng He, Linzhang Li, Chi Wang, Andrew N Lane, Ren Xu.

  Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.

Keywords:  cancer cell stemness; cell plasticity; collagen lysyl-hydroxylation; epithelial–mesenchymal transition; metabolite

DOI:  https://doi.org/10.1073/pnas.2214942120
Nat Metab. 2023 May 10.

Human metabolome variation along the upper intestinal tract.

Jacob Folz, Rebecca Neal Culver, Juan Montes Morales, Jessica Grembi, George Triadafilopoulos, David A Relman, Kerwyn Casey Huang, Dari Shalon, Oliver Fiehn.

Most processing of the human diet occurs in the small intestine. Metabolites in the small intestine originate from host secretions, plus the ingested exposome1 and microbial transformations. Here we probe the spatiotemporal variation of upper intestinal luminal contents during routine daily digestion in 15 healthy male and female participants. For this, we use a non-invasive, ingestible sampling device to collect and analyse 274 intestinal samples and 60 corresponding stool homogenates by combining five mass spectrometry assays2,3 and 16S rRNA sequencing. We identify 1,909 metabolites, including sulfonolipids and fatty acid esters of hydroxy fatty acids (FAHFA) lipids. We observe that stool and intestinal metabolomes differ dramatically. Food metabolites display trends in dietary biomarkers, unexpected increases in dicarboxylic acids along the intestinal tract and a positive association between luminal keto acids and fruit intake. Diet-derived and microbially linked metabolites account for the largest inter-individual differences. Notably, two individuals who had taken antibiotics within 6 months before sampling show large variation in levels of bioactive FAHFAs and sulfonolipids and other microbially related metabolites. From inter-individual variation, we identify Blautia species as a candidate to be involved in FAHFA metabolism. In conclusion, non-invasive, in vivo sampling of the human small intestine and ascending colon under physiological conditions reveals links between diet, host and microbial metabolism.

DOI: https://doi.org/10.1038/s42255-023-00777-z
Dev Cell. 2023 May 03. pii: S1534-5807(23)00180-6. [Epub ahead of print]

Immune mechanisms shape the clonal landscape during early progression of prostate cancer.

Lara F Tshering, Fu Luo, Savanah Russ, Mariola Szenk, Diana Rubel, Karis Tutuska, James G Rail, Gábor Balázsi, Michael M Shen, Flaminia Talos.

  Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Using multicolor lineage tracing in genetically engineered mouse models and single-cell transcriptomics, we show that slowly progressing tumors contain a multiclonal landscape of relatively homogeneous subpopulations within a well-organized tumor microenvironment. In more advanced and aggressive tumors, however, the multiclonal landscape develops into competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that this dominant/minor landscape is associated with differential immunoediting, in which minor clones are marked by an increased expression of IFNγ-response genes and the T cell-activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. Notably, the immune-specific gene signature of minor clones exhibits a prognostic value for biochemical recurrence-free survival in human prostate cancer. These findings suggest new immunotherapy approaches for modulating clonal fitness and tumor progression in prostate cancer.

Keywords:  clonal competition; immunoediting; prostate cancer; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.devcel.2023.04.010
Cell Rep. 2023 May 05. pii: S2211-1247(23)00492-8. [Epub ahead of print]42(5): 112481

MTHFD2 reprograms macrophage polarization by inhibiting PTEN.

Man Shang, Lina Ni, Xiao Shan, Yan Cui, Penghui Hu, Zemin Ji, Long Shen, Yanan Zhang, Jinxue Zhou, Bing Chen, Ting Wang, Qiujing Yu.

  The one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is involved in the regulation of tumor oncogenesis and immune cell functions, but whether it can contribute to macrophage polarization remains elusive. Here, we show that MTHFD2 suppresses polarization of interferon-γ-activated macrophages (M(IFN-γ)) but enhances that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, MTHFD2 interacts with phosphatase and tensin homolog (PTEN) to suppress PTEN's phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase activity and enhance downstream Akt activation, independent of the N-terminal mitochondria-targeting signal of MTHFD2. MTHFD2-PTEN interaction is promoted by IL-4 but not IFN-γ. Furthermore, amino acid residues (aa 215-225) of MTHFD2 directly target PTEN catalytic center (aa 118-141). Residue D168 of MTHFD2 is also critical for regulating PTEN's PIP3 phosphatase activity by affecting MTHFD2-PTEN interaction. Our study suggests a non-metabolic function of MTHFD2 by which MTHFD2 inhibits PTEN activity, orchestrates macrophage polarization, and alters macrophage-mediated immune responses.

Keywords:  CP: Immunology; MTHFD2; PTEN; macrophage polarization

DOI:  https://doi.org/10.1016/j.celrep.2023.112481
Nat Cell Biol. 2023 May 08.

Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function.

Ke Wu, Meisi Yan, Tong Liu, Zheng Wang, Yuran Duan, Yan Xia, Guimei Ji, Yuli Shen, Lei Wang, Lin Li, Peixiang Zheng, Bofei Dong, Qingang Wu, Liwei Xiao, Xueying Yang, Haochen Shen, Ting Wen, Jingjing Zhang, Jinfeng Yi, Yuhan Deng, Xu Qian, Leina Ma, Jing Fang, Qin Zhou, Zhimin Lu, Daqian Xu.

Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

DOI: https://doi.org/10.1038/s41556-023-01133-9
Nat Biotechnol. 2023 May 11.

A prime editor mouse to model a broad spectrum of somatic mutations in vivo.

Zackery A Ely, Nicolas Mathey-Andrews, Santiago Naranjo, Samuel I Gould, Kim L Mercer, Gregory A Newby, Christina M Cabana, William M Rideout, Grissel Cervantes Jaramillo, Jennifer M Khirallah, Katie Holland, Peyton B Randolph, William A Freed-Pastor, Jessie R Davis, Zachary Kulstad, Peter M K Westcott, Lin Lin, Andrew V Anzalone, Brendan L Horton, Nimisha B Pattada, Sean-Luc Shanahan, Zhongfeng Ye, Stefani Spranger, Qiaobing Xu, Francisco J Sánchez-Rivera, David R Liu, Tyler Jacks.

Genetically engineered mouse models only capture a small fraction of the genetic lesions that drive human cancer. Current CRISPR-Cas9 models can expand this fraction but are limited by their reliance on error-prone DNA repair. Here we develop a system for in vivo prime editing by encoding a Cre-inducible prime editor in the mouse germline. This model allows rapid, precise engineering of a wide range of mutations in cell lines and organoids derived from primary tissues, including a clinically relevant Kras mutation associated with drug resistance and Trp53 hotspot mutations commonly observed in pancreatic cancer. With this system, we demonstrate somatic prime editing in vivo using lipid nanoparticles, and we model lung and pancreatic cancer through viral delivery of prime editing guide RNAs or orthotopic transplantation of prime-edited organoids. We believe that this approach will accelerate functional studies of cancer-associated mutations and complex genetic combinations that are challenging to construct with traditional models.

DOI: https://doi.org/10.1038/s41587-023-01783-y
Cell Rep. 2023 May 11. pii: S2211-1247(23)00511-9. [Epub ahead of print]42(5): 112500

Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells.

Julie Lacombe, Kevin Guo, Jessica Bonneau, Denis Faubert, Florian Gioanni, Alexis Vivoli, Sarah M Muir, Soraya Hezzaz, Vincent Poitout, Mathieu Ferron.

  Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca2+-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca2+ overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+ flux in β cells and in their capacity to adapt to metabolic stress.

Keywords:  CP: Metabolism; ERGP; GGCX; diabetes; insulin secretion; store-operated calcium entry; vitamin K; β cells; γ-carboxylation

DOI:  https://doi.org/10.1016/j.celrep.2023.112500
Trends Biochem Sci. 2023 May 09. pii: S0968-0004(23)00086-5. [Epub ahead of print]

Insights into mitoribosomal biogenesis from recent structural studies.

Anas Khawaja, Miriam Cipullo, Annika Krüger, Joanna Rorbach.

  The mitochondrial ribosome (mitoribosome) is a multicomponent machine that has unique structural features. Biogenesis of the human mitoribosome includes correct maturation and folding of the mitochondria-encoded RNA components (12S and 16S mt-rRNAs, and mt-tRNAVal) and their assembly together with 82 nucleus-encoded mitoribosomal proteins. This complex process requires the coordinated action of multiple assembly factors. Recent advances in single-particle cryo-electron microscopy (cryo-EM) have provided detailed insights into the specific functions of several mitoribosome assembly factors and have defined their timing. In this review we summarize mitoribosomal small (mtSSU) and large subunit (mtLSU) biogenesis based on structural findings, and we discuss potential crosstalk between mtSSU and mtLSU assembly pathways as well as coordination between mitoribosome biogenesis and other processes involved in mitochondrial gene expression.

Keywords:  assembly factors; mitochondrial ribosome; mitoribosome assembly; ribosomal RNA

DOI:  https://doi.org/10.1016/j.tibs.2023.04.002
Nat Cancer. 2023 May 11.

A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression.

Bruce Culbertson, Kristle Garcia, Daniel Markett, Hosseinali Asgharian, Li Chen, Lisa Fish, Albertas Navickas, Johnny Yu, Brian Woo, Arjun Scott Nanda, Benedict Choi, Shaopu Zhou, Joshua Rabinowitz, Hani Goodarzi.

Antisense RNAs are ubiquitous in human cells, yet their role is largely unexplored. Here we profiled antisense RNAs in the MDA-MB-231 breast cancer cell line and its highly lung metastatic derivative. We identified one antisense RNA that drives cancer progression by upregulating the redox enzyme NADPH quinone dehydrogenase 1 (NQO1), and named it NQO1-AS. Knockdown of either NQO1 or NQO1-AS reduced lung colonization in a mouse model, and investigation into the role of NQO1 indicated that it is broadly protective against oxidative damage and ferroptosis. Breast cancer cells in the lung are dependent on this pathway, and this dependence can be exploited therapeutically by inducing ferroptosis while inhibiting NQO1. Together, our findings establish a role for NQO1-AS in the progression of breast cancer by regulating its sense mRNA post-transcriptionally. Because breast cancer predominantly affects females, the disease models used in this study are of female origin and the results are primarily applicable to females.

DOI: https://doi.org/10.1038/s43018-023-00554-7
Nat Commun. 2023 May 10. 14(1): 2692

Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.

Chenglong Sun, Anqiang Wang, Yanhe Zhou, Panpan Chen, Xiangyi Wang, Jianpeng Huang, Jiamin Gao, Xiao Wang, Liebo Shu, Jiawei Lu, Wentao Dai, Zhaode Bu, Jiafu Ji, Jiuming He.

Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated "tumor-normal interface" region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.

DOI: https://doi.org/10.1038/s41467-023-38360-5
Nat Cell Biol. 2023 May 11.

Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota.

Shimpei Kawamoto, Ken Uemura, Nozomi Hori, Lena Takayasu, Yusuke Konishi, Kazutaka Katoh, Tomonori Matsumoto, Masae Suzuki, Yusuke Sakai, Tatsuyuki Matsudaira, Takahiro Adachi, Naoko Ohtani, Daron M Standley, Wataru Suda, Shinji Fukuda, Eiji Hara.

The elucidation of the mechanisms of ageing and the identification of methods to control it have long been anticipated. Recently, two factors associated with ageing-the accumulation of senescent cells and the change in the composition of gut microbiota-have been shown to play key roles in ageing. However, little is known about how these phenomena occur and are related during ageing. Here we show that the persistent presence of commensal bacteria gradually induces cellular senescence in gut germinal centre B cells. Importantly, this reduces both the production and diversity of immunoglobulin A (IgA) antibodies that target gut bacteria, thereby changing the composition of gut microbiota in aged mice. These results have revealed the existence of IgA-mediated crosstalk between the gut microbiota and cellular senescence and thus extend our understanding of the mechanism of gut microbiota changes with age, opening up possibilities for their control.

DOI: https://doi.org/10.1038/s41556-023-01145-5