bims-camemi 2023-05-21 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023–05–21
forty-one papers selected by
Christian Frezza, Universität zu Köln

Impact of acute stress on murine metabolomics and metabolic flux.
A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.
Uridine-derived ribose fuels glucose-restricted pancreatic cancer.
RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome.
Emerging roles of nucleotide metabolism in cancer.
Lysine catabolism reprograms tumour immunity through histone crotonylation.
Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
Inflamed macrophages sans mitochondrial pyruvate carrier?
Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem.
Mitochondria are midfield players in steroid synthesis.
Human endogenous retrovirus onco-exaptation counters cancer cell senescence through Calbindin.
Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.
The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
IL4i1 and IDO1: oxidases that control a tryptophan metabolic nexus in cancer.
Lactate fuels mitosis.
Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
The free-living flagellate Paratrimastix pyriformis uses a distinct mitochondrial carrier to balance adenine nucleotide pools.
PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.
Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus.
Teasing out missing reactions in genome-scale metabolic networks through hypergraph learning.
Polarity signaling balances epithelial contractility and mechanical resistance.
MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.
Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
Intertwined regulation between RNA m6A modification and cancer metabolism.
Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance.
Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?
Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis.
LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
Crafting figures to describe cellular processes.
Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.
Writing and erasing ceramides to alter liver disease.
Hypoxia induces polycystin-1 expression in the renal epithelium.
Screen time: an unbiased search for histone mutations that affect quiescence and chronological aging.
Nerve-driven metastasis.
Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis.
Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice.
Hallmarks of cardiovascular ageing.
Cellular population dynamics shape the route to human pluripotency.
Subtle cell states resolved in single-cell data.
Singularity response reveals entrainment properties in mammalian circadian clock.

Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2301215120

Impact of acute stress on murine metabolomics and metabolic flux.

Won Dong Lee, Lingfan Liang, Jenna AbuSalim, Connor S R Jankowski, Laith Z Samarah, Michael D Neinast, Joshua D Rabinowitz.

  Plasma metabolite concentrations and labeling enrichments are common measures of organismal metabolism. In mice, blood is often collected by tail snip sampling. Here, we systematically examined the effect of such sampling, relative to gold-standard sampling from an in-dwelling arterial catheter, on plasma metabolomics and stable isotope tracing. We find marked differences between the arterial and tail circulating metabolome, which arise from two major factors: handling stress and sampling site, whose effects were deconvoluted by taking a second arterial sample immediately after tail snip. Pyruvate and lactate were the most stress-sensitive plasma metabolites, rising ~14 and ~5-fold. Both acute handling stress and adrenergic agonists induce extensive, immediate production of lactate, and modest production of many other circulating metabolites, and we provide a reference set of mouse circulatory turnover fluxes with noninvasive arterial sampling to avoid such artifacts. Even in the absence of stress, lactate remains the highest flux circulating metabolite on a molar basis, and most glucose flux into the TCA cycle in fasted mice flows through circulating lactate. Thus, lactate is both a central player in unstressed mammalian metabolism and strongly produced in response to acute stress.

Keywords:  catecholamine; in vivo; isotope tracing; metabolomics; stress

DOI:  https://doi.org/10.1073/pnas.2301215120
Sci Adv. 2023 May 19. 9(20): eadg2235

A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.

Niek Wit, Ewa Gogola, James A West, Tristan Vornbäumen, Rachel V Seear, Peter S J Bailey, Guillermo Burgos-Barragan, Meng Wang, Patrycja Krawczyk, Daphne H E W Huberts, Fanni Gergely, Nicholas J Matheson, Arthur Kaser, James A Nathan, Ketan J Patel.

Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite.

DOI: https://doi.org/10.1126/sciadv.adg2235
Nature. 2023 May 17.

Uridine-derived ribose fuels glucose-restricted pancreatic cancer.

Zeribe C Nwosu, Matthew H Ward, Peter Sajjakulnukit, Pawan Poudel, Chanthirika Ragulan, Steven Kasperek, Megan Radyk, Damien Sutton, Rosa E Menjivar, Anthony Andren, Juan J Apiz-Saab, Zachary Tolstyka, Kristee Brown, Ho-Joon Lee, Lindsey N Dzierozynski, Xi He, Hari Ps, Julia Ugras, Gift Nyamundanda, Li Zhang, Christopher J Halbrook, Eileen S Carpenter, Jiaqi Shi, Leah P Shriver, Gary J Patti, Alexander Muir, Marina Pasca di Magliano, Anguraj Sadanandam, Costas A Lyssiotis.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

DOI: https://doi.org/10.1038/s41586-023-06073-w
Nat Commun. 2023 May 15. 14(1): 2775

RagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome.

Irene Sambri, Marco Ferniani, Giulia Campostrini, Marialuisa Testa, Viviana Meraviglia, Mariana E G de Araujo, Ladislav Dokládal, Claudia Vilardo, Jlenia Monfregola, Nicolina Zampelli, Francesca Del Vecchio Blanco, Annalaura Torella, Carolina Ruosi, Simona Fecarotta, Giancarlo Parenti, Leopoldo Staiano, Milena Bellin, Lukas A Huber, Claudio De Virgilio, Francesco Trepiccione, Vincenzo Nigro, Andrea Ballabio.

Heterozygous mutations in the gene encoding RagD GTPase were shown to cause a novel autosomal dominant condition characterized by kidney tubulopathy and cardiomyopathy. We previously demonstrated that RagD, and its paralogue RagC, mediate a non-canonical mTORC1 signaling pathway that inhibits the activity of TFEB and TFE3, transcription factors of the MiT/TFE family and master regulators of lysosomal biogenesis and autophagy. Here we show that RagD mutations causing kidney tubulopathy and cardiomyopathy are "auto- activating", even in the absence of Folliculin, the GAP responsible for RagC/D activation, and cause constitutive phosphorylation of TFEB and TFE3 by mTORC1, without affecting the phosphorylation of "canonical" mTORC1 substrates, such as S6K. By using HeLa and HK-2 cell lines, human induced pluripotent stem cell-derived cardiomyocytes and patient-derived primary fibroblasts, we show that RRAGD auto-activating mutations lead to inhibition of TFEB and TFE3 nuclear translocation and transcriptional activity, which impairs the response to lysosomal and mitochondrial injury. These data suggest that inhibition of MiT/TFE factors plays a key role in kidney tubulopathy and cardiomyopathy syndrome.

DOI: https://doi.org/10.1038/s41467-023-38428-2
Trends Cancer. 2023 May 10. pii: S2405-8033(23)00064-X. [Epub ahead of print]

Emerging roles of nucleotide metabolism in cancer.

Diana D Shi, Milan R Savani, Kalil G Abdullah, Samuel K McBrayer.

  Nucleotides are substrates for multiple anabolic pathways, most notably DNA and RNA synthesis. Since nucleotide synthesis inhibitors began to be used for cancer therapy in the 1950s, our understanding of how nucleotides function in tumor cells has evolved, prompting a resurgence of interest in targeting nucleotide metabolism for cancer therapy. In this review, we discuss recent advances that challenge the idea that nucleotides are mere building blocks for the genome and transcriptome and highlight ways that these metabolites support oncogenic signaling, stress resistance, and energy homeostasis in tumor cells. These findings point to a rich network of processes sustained by aberrant nucleotide metabolism in cancer and reveal new therapeutic opportunities.

Keywords:  metabolism; nucleotides; purines; pyrimidines

DOI:  https://doi.org/10.1016/j.trecan.2023.04.008
Nature. 2023 May 17.

Lysine catabolism reprograms tumour immunity through histone crotonylation.

Huairui Yuan, Xujia Wu, Qiulian Wu, Adam Chatoff, Emily Megill, Jinjun Gao, Tengfei Huang, Tingting Duan, Kailin Yang, Chunyu Jin, Fanen Yuan, Shuai Wang, Linjie Zhao, Pascal O Zinn, Kalil G Abdullah, Yingming Zhao, Nathaniel W Snyder, Jeremy N Rich.

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3-5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8+ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.

DOI: https://doi.org/10.1038/s41586-023-06061-0
Cells. 2023 05 06. pii: 1329. [Epub ahead of print]12(9):

Cellular and Mitochondrial NAD Homeostasis in Health and Disease.

Jaylyn Waddell, Rehana Khatoon, Tibor Kristian.

  The mitochondrion has a unique position among other cellular organelles due to its dynamic properties and symbiotic nature, which is reflected in an active exchange of metabolites and cofactors between the rest of the intracellular compartments. The mitochondrial energy metabolism is greatly dependent on nicotinamide adenine dinucleotide (NAD) as a cofactor that is essential for both the activity of respiratory and TCA cycle enzymes. The NAD level is determined by the rate of NAD synthesis, the activity of NAD-consuming enzymes, and the exchange rate between the individual subcellular compartments. In this review, we discuss the NAD synthesis pathways, the NAD degradation enzymes, and NAD subcellular localization, as well as NAD transport mechanisms with a focus on mitochondria. Finally, the effect of the pathologic depletion of mitochondrial NAD pools on mitochondrial proteins' post-translational modifications and its role in neurodegeneration will be reviewed. Understanding the physiological constraints and mechanisms of NAD maintenance and the exchange between subcellular compartments is critical given NAD's broad effects and roles in health and disease.

Keywords:  NAD; brain; mitochondria

DOI:  https://doi.org/10.3390/cells12091329
Nat Metab. 2023 May 15.

Inflamed macrophages sans mitochondrial pyruvate carrier?

Laurent Yvan-Charvet, Edward Benjamin Thorp.

DOI: https://doi.org/10.1038/s42255-023-00789-9
Nat Commun. 2023 May 19. 14(1): 2876

Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem.

Michaela Schwaiger-Haber, Ethan Stancliffe, Dhanalakshmi S Anbukumar, Blake Sells, Jia Yi, Kevin Cho, Kayla Adkins-Travis, Milan G Chheda, Leah P Shriver, Gary J Patti.

Tumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix assisted laser desorption ionization reveals alterations in multiple anabolic pathways. De novo fatty acid synthesis flux is increased by approximately 3-fold in glioma relative to surrounding healthy tissue. Fatty acid elongation flux is elevated even higher at 8-fold relative to surrounding healthy tissue and highlights the importance of elongase activity in glioma.

DOI: https://doi.org/10.1038/s41467-023-38403-x
Int J Biochem Cell Biol. 2023 May 17. pii: S1357-2725(23)00070-5. [Epub ahead of print] 106431

Mitochondria are midfield players in steroid synthesis.

Philipp Melchinger, Bruna Martins Garcia.

  Steroids are important membrane components and signaling metabolites and thus are required for cellular homeostasis. All mammalian cells retain the ability to uptake and synthesize steroids. Dysregulation of steroid levels leads to profound effects on cellular function and organismal health. Hence it comes as no surprise that steroid synthesis is tightly regulated. It is well established that the main site for steroid synthesis and regulation is the endoplasmic reticulum. However, mitochondria are essential for: (1) cholesterol production (the precursor of all steroids) by exporting citrate and; (2) the products of steroidogenesis (such as mineralocorticoids and glucocorticoids). In this review, we describe the midfield player role of mitochondria in steroid synthesis and bring the idea of mitochondria actively participating in steroid synthesis regulation. A better understanding of the mitochondrial regulatory roles in steroid synthesis would open new avenues to targeted approaches aiming to control steroid levels.

Keywords:  Cholesterol synthesis; Mitochondria-ER contact; Steroid hormones

DOI:  https://doi.org/10.1016/j.biocel.2023.106431
J Clin Invest. 2023 May 16. pii: e164397. [Epub ahead of print]

Human endogenous retrovirus onco-exaptation counters cancer cell senescence through Calbindin.

Jan Attig, Judith Pape, Laura Doglio, Anastasiya Kazachenka, Eleonora Ottina, George R Young, Katey Ss Enfield, Iker Valle Aramburu, Kevin W Ng, Nikhil Faulkner, William Bolland, Venizelos Papayannopoulos, Charles Swanton, George Kassiotis.

  Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterizes most cancer types, linked with disease outcomes. However, the underlying processes are incompletely understood. We show that elevated transcription of HERVH proviruses predicts survival of lung squamous cell carcinoma (LUSC) and identify an isoform of CALB1, encoding Calbindin, ectopically driven by an upstream HERVH provirus under the control of KLF5, as the mediator of this effect. HERVH-CALB1 expression initiates in pre-invasive lesions and associates with their progression. Calbindin loss in LUSC cell lines impairs in vitro and in vivo growth and triggers senescence, consistent with a pro-tumor effect. However, Calbindin also directly controls the senescence-associated secretory phenotype (SASP), marked by secretion of CXCL8 and other neutrophil chemoattractants. In established carcinomas, CALB1-negative cancer cells become the dominant source of CXCL8, correlating with neutrophil infiltration and worse prognosis. Thus, HERVH-CALB1 expression in LUSC may display antagonistic pleiotropy, whereby the benefits of escaping senescence early during cancer initiation and clonal competition are offset by the prevention of SASP and pro-tumor inflammation at later stages.

Keywords:  Cellular senescence; Epigenetics; Genetics; Lung cancer; Oncology

DOI:  https://doi.org/10.1172/JCI164397
Nat Metab. 2023 May 17.

Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.

Owen S Skinner, Joan Blanco-Fernández, Russell P Goodman, Akinori Kawakami, Hongying Shen, Lajos V Kemény, Lena Joesch-Cohen, Matthew G Rees, Jennifer A Roth, David E Fisher, Vamsi K Mootha, Alexis A Jourdain.

Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency1, our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that 'uridine bypass' of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes.

DOI: https://doi.org/10.1038/s42255-023-00774-2
Mol Cell. 2023 May 06. pii: S1097-2765(23)00316-7. [Epub ahead of print]

The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.

Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Shun-Ichi Yamashita, Daisuke Noshiro, Chihong Song, Yuta Ogasawara, Kentaro Okuyama, Jahangir Md Alam, Manabu Hayatsu, Tetsu Saigusa, Keiichi Inoue, Kazuho Ikeda, Akira Takai, Lin Chen, Vikramjit Lahiri, Yasushi Okada, Shinsuke Shibata, Kazuyoshi Murata, Daniel J Klionsky, Nobuo N Noda, Tomotake Kanki.

  Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.

Keywords:  Atg44; autophagy; crystal structure analysis; dynamin-related protein; high-speed atomic force microscopy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast

DOI:  https://doi.org/10.1016/j.molcel.2023.04.022
J Biol Chem. 2023 May 15. pii: S0021-9258(23)01855-0. [Epub ahead of print] 104827

IL4i1 and IDO1: oxidases that control a tryptophan metabolic nexus in cancer.

Leonie Zeitler, Peter J Murray.

Regulated tryptophan metabolism by immune cells has been associated with the promotion of tolerance and poor outcomes in cancer. The main focus of research has centered on local tryptophan depletion by IDO1, an intracellular heme-dependent oxidase that converts tryptophan to formyl-kynurenine. This is the first step of a complex pathway supplying metabolites for de novo NAD+ biosynthesis, 1-carbon metabolism and a myriad of kynurenine derivatives, of which several act as agonists of the arylhydrocarbon receptor (AhR). Thus, cells that express IDO1 deplete tryptophan while generating downstream metabolites. We now know that another enzyme, the secreted L-amino acid oxidase IL4i1, also generates bioactive metabolites from tryptophan. In tumor microenvironments, IL4i1 and IDO1 have overlapping expression patterns, especially in myeloid cells, suggesting the two enzymes control a network of tryptophan-specific metabolic events. New findings about IL4i1 and IDO1 have shown that both enzymes generate a suite of metabolites that suppress the oxidative cell death ferroptosis. Thus, within inflammatory environments, IL4i1 and IDO1 simultaneously control essential amino acid depletion, AhR activation, suppression of ferroptosis and biosynthesis of key metabolic intermediates. Here, we summarize the recent advances in this field, focusing on IDO1 and IL4i1 in cancer. We speculate that while inhibition of IDO1 remains a viable adjuvant therapy for solid tumors, the overlapping effects of IL4i1 must be accounted for, as potentially both enzymes may need to be inhibited at the same time to produce positive effects in cancer therapy.

DOI: https://doi.org/10.1016/j.jbc.2023.104827
Mol Cell. 2023 May 18. pii: S1097-2765(23)00284-8. [Epub ahead of print]83(10): 1549-1551

Lactate fuels mitosis.

Xiaoming Dai, Wenyi Wei.

Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al.1 reveal that glycolysis end-product lactate directly binds and inhibits the SUMO protease SENP1 to govern the E3 ligase activity of the anaphase-promoting complex, leading to efficient mitotic exit in proliferative cells.

DOI: https://doi.org/10.1016/j.molcel.2023.04.013
Sci Transl Med. 2023 May 17. 15(696): eade6509

Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.

Tanes I Lima, Pirkka-Pekka Laurila, Martin Wohlwend, Jean David Morel, Ludger J E Goeminne, Hao Li, Mario Romani, Xiaoxu Li, Chang-Myung Oh, Dohyun Park, Sandra Rodríguez-López, Julijana Ivanisevic, Hector Gallart-Ayala, Barbara Crisol, Florence Delort, Sabrina Batonnet-Pichon, Leonardo R Silveira, Lakshmi Sankabattula Pavani Veera Venkata, Anil K Padala, Suresh Jain, Johan Auwerx.

Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that ceramide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Analysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored proteostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related proteinopathies via mitochondrial and proteostasis remodeling.

DOI: https://doi.org/10.1126/scitranslmed.ade6509
Arch Biochem Biophys. 2023 May 14. pii: S0003-9861(23)00137-6. [Epub ahead of print] 109638

The free-living flagellate Paratrimastix pyriformis uses a distinct mitochondrial carrier to balance adenine nucleotide pools.

Justyna Zítek, Martin S King, Priscila Peña-Diaz, Eva Pyrihová, Alannah C King, Edmund R S Kunji, Vladimír Hampl.

  Paratrimastix pyriformis is a free-living flagellate thriving in low-oxygen freshwater sediments. It belongs to the group Metamonada along with human parasites, such as Giardia and Trichomonas. Like other metamonads, P. pyriformis has a mitochondrion-related organelle (MRO) which in this protist is primarily involved in one-carbon folate metabolism. The MRO contains four members of the solute carrier family 25 (SLC25) responsible for the exchange of metabolites across the mitochondrial inner membrane. Here, we characterise the function of the adenine nucleotide carrier PpMC1 by thermostability shift and transport assays. We show that it transports ATP, ADP and, to a lesser extent, AMP, but not phosphate. The carrier is distinct in function and origin from both ADP/ATP carriers and ATP-Mg/phosphate carriers, and it most likely represents a distinct class or classes of adenine nucleotide carriers.

Keywords:  Mitochondrial carrier; Mitochondrion-related organelle; Nucleoside/nucleotide transport; Paratrimastix pyriformis

DOI:  https://doi.org/10.1016/j.abb.2023.109638
Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2217826120

PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.

Bo Kyung Yoon, Hyeonhui Kim, Tae Gyu Oh, Se Kyu Oh, Sugyeong Jo, Minki Kim, Kyu-Hye Chun, Nahee Hwang, Suji Lee, Suyon Jin, Annette R Atkins, Ruth T Yu, Michael Downes, Jae-Woo Kim, Hyunkyung Kim, Ronald M Evans, Jae-Ho Cheong, Sungsoon Fang.

  Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.

Keywords:  3 phosphoglycerate dehydrogenase; gastric cancer; glutaminase; metabolic plasticity

DOI:  https://doi.org/10.1073/pnas.2217826120
Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2301330120

Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus.

Andrew P Patton, Emma L Morris, David McManus, Huan Wang, Yulong Li, Jason W Chin, Michael H Hastings.

  The hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity, which in turn control circadian behavior. Intercellular signals, mediated by neuropeptides, synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level timekeeping is unclear. How can a GABAergic circuit sustain circadian cycles of electrical activity, when such increased neuronal firing should become inhibitory to the network? To explore this paradox, we show that SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counterintuitively, runs in antiphase to neuronal activity, with a prolonged peak in circadian night and a pronounced trough in circadian day. Resolving this unexpected relationship, we found that [GABA]e is regulated by GABA transporters (GATs), with uptake peaking during circadian day, hence the daytime trough and nighttime peak. This uptake is mediated by the astrocytically expressed transporter GAT3 (Slc6a11), expression of which is circadian-regulated, being elevated in daytime. Clearance of [GABA]e in circadian day facilitates neuronal firing and is necessary for circadian release of the neuropeptide vasoactive intestinal peptide, a critical regulator of TTFL and circuit-level rhythmicity. Finally, we show that genetic complementation of the astrocytic TTFL alone, in otherwise clockless SCN, is sufficient to drive [GABA]e rhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.

Keywords:  GABA; GABA transporters; astrocytes; circadian rhythms; suprachiasmatic nucleus

DOI:  https://doi.org/10.1073/pnas.2301330120
Nat Commun. 2023 Apr 25. 14(1): 2375

Teasing out missing reactions in genome-scale metabolic networks through hypergraph learning.

Can Chen, Chen Liao, Yang-Yu Liu.

GEnome-scale Metabolic models (GEMs) are powerful tools to predict cellular metabolism and physiological states in living organisms. However, due to our imperfect knowledge of metabolic processes, even highly curated GEMs have knowledge gaps (e.g., missing reactions). Existing gap-filling methods typically require phenotypic data as input to tease out missing reactions. We still lack a computational method for rapid and accurate gap-filling of metabolic networks before experimental data is available. Here we present a deep learning-based method - CHEbyshev Spectral HyperlInk pREdictor (CHESHIRE) - to predict missing reactions in GEMs purely from metabolic network topology. We demonstrate that CHESHIRE outperforms other topology-based methods in predicting artificially removed reactions over 926 high- and intermediate-quality GEMs. Furthermore, CHESHIRE is able to improve the phenotypic predictions of 49 draft GEMs for fermentation products and amino acids secretions. Both types of validation suggest that CHESHIRE is a powerful tool for GEM curation to reveal unknown links between reactions and observed metabolic phenotypes.

DOI: https://doi.org/10.1038/s41467-023-38110-7
Sci Rep. 2023 May 12. 13(1): 7743

Polarity signaling balances epithelial contractility and mechanical resistance.

Matthias Rübsam, Robin Püllen, Frederik Tellkamp, Alessandra Bianco, Marc Peskoller, Wilhelm Bloch, Kathleen J Green, Rudolf Merkel, Bernd Hoffmann, Sara A Wickström, Carien M Niessen.

Epithelia maintain a functional barrier during tissue turnover while facing varying mechanical stress. This maintenance requires both dynamic cell rearrangements driven by actomyosin-linked intercellular adherens junctions and ability to adapt to and resist extrinsic mechanical forces enabled by keratin filament-linked desmosomes. How these two systems crosstalk to coordinate cellular movement and mechanical resilience is not known. Here we show that in stratifying epithelia the polarity protein aPKCλ controls the reorganization from stress fibers to cortical actomyosin during differentiation and upward movement of cells. Without aPKC, stress fibers are retained resulting in increased contractile prestress. This aberrant stress is counterbalanced by reorganization and bundling of keratins, thereby increasing mechanical resilience. Inhibiting contractility in aPKCλ-/- cells restores normal cortical keratin networks but also normalizes resilience. Consistently, increasing contractile stress is sufficient to induce keratin bundling and enhance resilience, mimicking aPKC loss. In conclusion, our data indicate that keratins sense the contractile stress state of stratified epithelia and balance increased contractility by mounting a protective response to maintain tissue integrity.

DOI: https://doi.org/10.1038/s41598-023-33485-5
Mitochondrion. 2023 May 10. pii: S1567-7249(23)00038-7. [Epub ahead of print]

MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.

Jeremy Michelson, Shannon Rausser, Amanda Peng, Temmie Yu, Gabriel Sturm, Caroline Trumpff, Brett A Kaufman, Alex J Rai, Martin Picard.

  Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states. To evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. Here, we describe MitoQuicLy: Mitochondrial DNA Quantification in cell-free samples by Lysis. We demonstrate high agreement between MitoQuicLy and the commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. Using 10 µL of input volume with MitoQuicLy, we quantify cf-mtDNA levels from three commonly used plasma tube types, two serum tube types, and saliva. We detect, as expected, significant inter-individual differences in cf-mtDNA across different biofluids. However, cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings. Moreover, in a small sample of healthy women and men (n=34), we show that blood and saliva cf-mtDNAs correlate with clinical biomarkers differently depending on the sample used. The biological divergences revealed between biofluids, together with the lysis-based, cost-effective, and scalable MitoQuicLy protocol for biofluid cf-mtDNA quantification, provide a foundation to examine the biological origin and significance of cf-mtDNA to human health.

Keywords:  Cell-free DNA; Circulating nucleic acids; DNA isolation; Mitochondria; Mitochondrial DNA; Protocol

DOI:  https://doi.org/10.1016/j.mito.2023.05.001
Cell Metab. 2023 May 05. pii: S1550-4131(23)00171-7. [Epub ahead of print]

Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.

Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang.

  Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.

Keywords:  CD8(+) T cell activation; FH; ZAP70; anti-tumor immune response; fumarate; fumarate hydrolase; succination; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2023.04.017
Cell Insight. 2023 Feb;2(1): 100075

Intertwined regulation between RNA m6A modification and cancer metabolism.

Jiaxu Liu, Hao Huang, Minghao Zhang, Guoliang Qing, Hudan Liu.

RNA N6-methyladenosine (m6A) has been identified as the most common, abundant and conserved internal modification in RNA transcripts, especially within eukaryotic messenger RNAs (mRNAs). Accumulating evidence demonstrates that RNA m6A modification exploits a wide range of regulatory mechanisms to control gene expression in pathophysiological processes including cancer. Metabolic reprogramming has been widely recognized as a hallmark of cancer. Cancer cells obtain metabolic adaptation through a variety of endogenous and exogenous signaling pathways to promote cell growth and survival in the microenvironment with limited nutrient supply. Recent emerging evidence reveals reciprocal regulation between the m6A modification and disordered metabolic events in cancer cells, adding more complexity in the cellular network of metabolic rewiring. In this review, we summarize the most recent advances of how RNA methylation affects tumor metabolism and the feedback regulation of m6A modification by metabolic intermediates. We aim to highlight the important connection between RNA m6A modification and cancer metabolism, and expect that studise of RNA m6A and metabolic reprogramming will lead to greater understanding of cancer pathology.

DOI: https://doi.org/10.1016/j.cellin.2022.100075
bioRxiv. 2023 Mar 30. pii: 2023.03.29.534718. [Epub ahead of print]

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance.

Joshua D Bernstock, Cory M Willis, Monica Emili Garcia-Segura, Edoardo Gaude, Daniela Anni, Yan-Ja Lee, Luke W Thomas, Alva Casey, Nunzio Vicario, Tommaso Leonardi, Alexandra M Nicaise, Florian A Gessler, Saef Izzy, Mario R Buffelli, Jakob Seidlitz, Shriya Srinivasan, Michael P Murphy, Margaret Ashcroft, Marco Cambiaghi, John M Hallenbeck, Luca Peruzzotti-Jametti.

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

DOI: https://doi.org/10.1101/2023.03.29.534718
Cell Calcium. 2023 May 11. pii: S0143-4160(23)00069-6. [Epub ahead of print]113 102757

Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?

Paloma Garcia-Casas, Michela Rossini, Riccardo Filadi, Paola Pizzo.

  Alzheimer's disease (AD) is a neurodegenerative disease, caused by poorly known pathogenic mechanisms and aggravated by delayed therapeutic intervention, that still lacks an effective cure. However, it is clear that some important neurophysiological processes are altered years before the onset of clinical symptoms, offering the possibility of identifying biological targets useful for implementation of new therapies. Of note, evidence has been provided suggesting that mitochondria, pivotal organelles in sustaining neuronal energy demand and modulating synaptic activity, are dysfunctional in AD samples. In particular, alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegeneration, although the exact outcomes and molecular mechanisms of these defects, as well as their longitudinal progression, are not always clear. Here, we discuss the importance of a correct mitochondrial Ca2+ handling for neuronal physiology and summarize the latest findings on dysfunctional mitochondrial Ca2+ pathways in AD, analysing possible consequences contributing to the neurodegeneration that characterizes the disease.

Keywords:  Alzheimer's disease; ER-mitochondria contacts; MCU; Mitochondrial calcium signaling; NCLX; Presenilin

DOI:  https://doi.org/10.1016/j.ceca.2023.102757
Cell Chem Biol. 2023 May 04. pii: S2451-9456(23)00114-9. [Epub ahead of print]

Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis.

Joseph M Hendricks, Cody E Doubravsky, Eddie Wehri, Zhipeng Li, Melissa A Roberts, Kirandeep K Deol, Mike Lange, Irene Lasheras-Otero, Jeremiah D Momper, Scott J Dixon, Kirill Bersuker, Julia Schaletzky, James A Olzmann.

  Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of phospholipid hydroperoxides. Inducing ferroptosis is a promising approach to treat therapy-resistant cancer. Ferroptosis suppressor protein 1 (FSP1) promotes ferroptosis resistance in cancer by generating the antioxidant form of coenzyme Q10 (CoQ). Despite the important role of FSP1, few molecular tools exist that target the CoQ-FSP1 pathway. Through a series of chemical screens, we identify several structurally diverse FSP1 inhibitors. The most potent of these compounds, ferroptosis sensitizer 1 (FSEN1), is an uncompetitive inhibitor that acts selectively through on-target inhibition of FSP1 to sensitize cancer cells to ferroptosis. Furthermore, a synthetic lethality screen reveals that FSEN1 synergizes with endoperoxide-containing ferroptosis inducers, including dihydroartemisinin, to trigger ferroptosis. These results provide new tools that catalyze the exploration of FSP1 as a therapeutic target and highlight the value of combinatorial therapeutic regimes targeting FSP1 and additional ferroptosis defense pathways.

Keywords:  FSP1; GPX4; cancer; cell death; coenzyme Q10; endoperoxide; ferroptosis; glutathione; lipid peroxidation; small molecule screen

DOI:  https://doi.org/10.1016/j.chembiol.2023.04.007
Mol Cell. 2023 May 02. pii: S1097-2765(23)00288-5. [Epub ahead of print]

LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

Shelby E Compton, Susan M Kitchen-Goosen, Lisa M DeCamp, Kin H Lau, Batsirai Mabvakure, Matthew Vos, Kelsey S Williams, Kwok-Kin Wong, Xiaobing Shi, Scott B Rothbart, Connie M Krawczyk, Russell G Jones.

  Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.

Keywords:  CREB; CREB-regulated transcription coactivator 2; CRTC2; H3K27; IL-1β; IL-6; LIF; LKB1; SIKs; cAMP response element binding protein; histone acetylation; inflammation; interleukin-6; leukemia inhibitory factor; liver kinase B1; salt-inducible kinases

DOI:  https://doi.org/10.1016/j.molcel.2023.04.017
Trends Biochem Sci. 2023 Jun;pii: S0968-0004(22)00241-9. [Epub ahead of print]48(6): 491-494

Crafting figures to describe cellular processes.

Szymon W Kmiecik, Qiaoni Shi, Ye-Guang Chen, Jannis Moormann, Tatjana M Hildebrandt, Amy Schade, Martin Fischer, Kyusik Q Kim.

DOI: https://doi.org/10.1016/j.tibs.2022.09.004
Cell. 2023 May 11. pii: S0092-8674(23)00422-1. [Epub ahead of print]

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Junbing Zhang, Claire M Simpson, Jacqueline Berner, Harrison B Chong, Jiafeng Fang, Zehra Ordulu, Tommy Weiss-Sadan, Anthony P Possemato, Stefan Harry, Mariko Takahashi, Tzu-Yi Yang, Marianne Richter, Himani Patel, Abby E Smith, Alexander D Carlin, Adriaan F Hubertus de Groot, Konstantin Wolf, Lei Shi, Ting-Yu Wei, Benedikt R Dürr, Nicholas J Chen, Tristan Vornbäumen, Nina O Wichmann, Mohammed S Mahamdeh, Venkatesh Pooladanda, Yusuke Matoba, Shaan Kumar, Eugene Kim, Sara Bouberhan, Esther Oliva, Bo R Rueda, Roy J Soberman, Nabeel Bardeesy, Brian B Liau, Michael Lawrence, Matt P Stokes, Sean A Beausoleil, Liron Bar-Peled.

  Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Keywords:  CHK1; chemical proteomics; chemoresistance; mitochondrial translation; nuclear ROS; nucleus-to-mitochondria signaling

DOI:  https://doi.org/10.1016/j.cell.2023.04.026
Nat Metab. 2023 May 15.

Writing and erasing ceramides to alter liver disease.

Mariah Weber-Stout, Scott A Summers, William L Holland.

DOI: https://doi.org/10.1038/s42255-023-00809-8
R Soc Open Sci. 2023 May;10(5): 220992

Hypoxia induces polycystin-1 expression in the renal epithelium.

Steffen Grampp, Andre Kraus, Kathrin Skoczynski, Mario Schiffer, René Krüger, Stephanie Naas, Johannes Schödel, Bjoern Buchholz.

  Mutations in polycystin-1 which is encoded by the PKD1 gene are the main causes for the development of autosomal dominant polycystic kidney disease. However, only little is known about the physiological function of polycystin-1 and even less about the regulation of its expression. Here, we show that expression of PKD1 is induced by hypoxia and compounds that stabilize the hypoxia-inducible transcription factor (HIF) 1α in primary human tubular epithelial cells. Knockdown of HIF subunits confirms HIF-1α-dependent regulation of polycystin-1 expression. Furthermore, HIF ChIP-seq reveals that HIF interacts with a regulatory DNA element within the PKD1 gene in renal tubule-derived cells. HIF-dependent expression of polycystin-1 can also be demonstrated in vivo in kidneys of mice treated with substances that stabilize HIF. Polycystin-1 and HIF-1α have been shown to promote epithelial branching during kidney development. In line with these findings, we show that expression of polycystin-1 within mouse embryonic ureteric bud branches is regulated by HIF. Our finding links expression of one of the main regulators of accurate renal development with the hypoxia signalling pathway and provides additional insight into the pathophysiology of polycystic kidney disease.

Keywords:  PKD1; hypoxia; hypoxia-inducible factor; kidney development; polycystic kidney disease; transcription regulation

DOI:  https://doi.org/10.1098/rsos.220992
FEBS J. 2023 May 15.

Screen time: an unbiased search for histone mutations that affect quiescence and chronological aging.

Mithun Mitra, Hilary A Coller.

  Quiescence, reversible cell cycle arrest, is essential for survival during nutrient limitations and the execution of precise developmental patterns. In yeast, entry into quiescence is associated with a loss of histone acetylation as the chromatin becomes tightly condensed. In this issue, Small and Osley performed an unbiased screen of mutations in histone H3 and H4 amino acids in budding yeast and identified histone residues that are critical for quiescence and chronological lifespan. The results indicate that multiple histone amino acids, likely affecting nucleosome structure and a wide range of chromatin-associated processes, can promote or inhibit quiescence entry. Many of the same histone amino acids are also critical regulators of chronological lifespan.

Keywords:  chromatin; chronological lifespan; histone post-translational modifications; quiescence; transcription

DOI:  https://doi.org/10.1111/febs.16788
Nat Rev Cancer. 2023 May 17.

Nerve-driven metastasis.

Daniela Senft.

DOI: https://doi.org/10.1038/s41568-023-00588-0
Nat Commun. 2023 May 13. 14(1): 2759

Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis.

Lindsey R Conroy, Harrison A Clarke, Derek B Allison, Samuel Santos Valenca, Qi Sun, Tara R Hawkinson, Lyndsay E A Young, Juanita E Ferreira, Autumn V Hammonds, Jaclyn B Dunne, Robert J McDonald, Kimberly J Absher, Brittany E Dong, Ronald C Bruntz, Kia H Markussen, Jelena A Juras, Warren J Alilain, Jinze Liu, Matthew S Gentry, Peggi M Angel, Christopher M Waters, Ramon C Sun.

Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis when compared to WT animals. Collectively, we provide conclusive evidence that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. In summary, our study provides a roadmap to leverage spatial metabolomics to understand foundational biology in pulmonary diseases.

DOI: https://doi.org/10.1038/s41467-023-38437-1
Nat Metab. 2023 May 15.

Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.

Linyu Ran, Song Zhang, Guosheng Wang, Pei Zhao, Jiaxing Sun, Jiaqi Zhou, Haiyun Gan, Ryounghoon Jeon, Qiang Li, Joerg Herrmann, Feilong Wang.

Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.

DOI: https://doi.org/10.1038/s42255-023-00800-3
Nat Metab. 2023 May 15.

m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice.

Shiguan Wang, Shanze Chen, Jianfeng Sun, Pan Han, Bowen Xu, Xinying Li, Youquan Zhong, Zaichao Xu, Peng Zhang, Ping Mi, Cuijuan Zhang, Lixiang Li, Haiyan Zhang, Yuchen Xia, Shiyang Li, Mathias Heikenwalder, Detian Yuan.

Different organs undergo distinct transcriptional, epigenetic and physiological alterations that guarantee their functional maturation after birth. However, the roles of epitranscriptomic machineries in these processes have remained elusive. Here we demonstrate that expression of RNA methyltransferase enzymes Mettl3 and Mettl14 gradually declines during postnatal liver development in male mice. Liver-specific Mettl3 deficiency causes hepatocyte hypertrophy, liver injury and growth retardation. Transcriptomic and N6-methyl-adenosine (m6A) profiling identify the neutral sphingomyelinase, Smpd3, as a target of Mettl3. Decreased decay of Smpd3 transcripts due to Mettl3 deficiency results in sphingolipid metabolism rewiring, characterized by toxic ceramide accumulation and leading to mitochondrial damage and elevated endoplasmic reticulum stress. Pharmacological Smpd3 inhibition, Smpd3 knockdown or Sgms1 overexpression that counteracts Smpd3 can ameliorate the abnormality of Mettl3-deficent liver. Our findings demonstrate that Mettl3-N6-methyl-adenosine fine-tunes sphingolipid metabolism, highlighting the pivotal role of an epitranscriptomic machinery in coordination of organ growth and the timing of functional maturation during postnatal liver development.

DOI: https://doi.org/10.1038/s42255-023-00808-9
Nat Rev Cardiol. 2023 May 16.

Hallmarks of cardiovascular ageing.

Mahmoud Abdellatif, Peter P Rainer, Simon Sedej, Guido Kroemer.

Normal circulatory function is a key determinant of disease-free life expectancy (healthspan). Indeed, pathologies affecting the cardiovascular system, which are growing in prevalence, are the leading cause of global morbidity, disability and mortality, whereas the maintenance of cardiovascular health is necessary to promote both organismal healthspan and lifespan. Therefore, cardiovascular ageing might precede or even underlie body-wide, age-related health deterioration. In this Review, we posit that eight molecular hallmarks are common denominators in cardiovascular ageing, namely disabled macroautophagy, loss of proteostasis, genomic instability (in particular, clonal haematopoiesis of indeterminate potential), epigenetic alterations, mitochondrial dysfunction, cell senescence, dysregulated neurohormonal signalling and inflammation. We also propose a hierarchical order that distinguishes primary (upstream) from antagonistic and integrative (downstream) hallmarks of cardiovascular ageing. Finally, we discuss how targeting each of the eight hallmarks might be therapeutically exploited to attenuate residual cardiovascular risk in older individuals.

DOI: https://doi.org/10.1038/s41569-023-00881-3
Nat Commun. 2023 May 17. 14(1): 2829

Cellular population dynamics shape the route to human pluripotency.

Francesco Panariello, Onelia Gagliano, Camilla Luni, Antonio Grimaldi, Silvia Angiolillo, Wei Qin, Anna Manfredi, Patrizia Annunziata, Shaked Slovin, Lorenzo Vaccaro, Sara Riccardo, Valentina Bouche, Manuela Dionisi, Marcello Salvi, Sebastian Martewicz, Manli Hu, Meihua Cui, Hannah Stuart, Cecilia Laterza, Giacomo Baruzzo, Geoffrey Schiebinger, Barbara Di Camillo, Davide Cacchiarelli, Nicola Elvassore.

Human cellular reprogramming to induced pluripotency is still an inefficient process, which has hindered studying the role of critical intermediate stages. Here we take advantage of high efficiency reprogramming in microfluidics and temporal multi-omics to identify and resolve distinct sub-populations and their interactions. We perform secretome analysis and single-cell transcriptomics to show functional extrinsic pathways of protein communication between reprogramming sub-populations and the re-shaping of a permissive extracellular environment. We pinpoint the HGF/MET/STAT3 axis as a potent enhancer of reprogramming, which acts via HGF accumulation within the confined system of microfluidics, and in conventional dishes needs to be supplied exogenously to enhance efficiency. Our data suggest that human cellular reprogramming is a transcription factor-driven process that it is deeply dependent on extracellular context and cell population determinants.

DOI: https://doi.org/10.1038/s41467-023-37270-w
Nat Biotechnol. 2023 May 17.

Subtle cell states resolved in single-cell data.

Caleb Lareau.

DOI: https://doi.org/10.1038/s41587-023-01797-6
Nat Commun. 2023 May 17. 14(1): 2819

Singularity response reveals entrainment properties in mammalian circadian clock.

Kosaku Masuda, Naohiro Kon, Kosuke Iizuka, Yoshitaka Fukada, Takeshi Sakurai, Arisa Hirano.

Entrainment is characterized by phase response curves (PRCs), which provide a summary of responses to perturbations at each circadian phase. The synchronization of mammalian circadian clocks is accomplished through the receipt of a variety of inputs from both internal and external time cues. A comprehensive comparison of PRCs for various stimuli in each tissue is required. Herein, we demonstrate that PRCs in mammalian cells can be characterized using a recently developed estimation method based on singularity response (SR), which represents the response of desynchronized cellular clocks. We confirmed that PRCs can be reconstructed using single SR measurements and quantified response properties for various stimuli in several cell lines. SR analysis reveals that the phase and amplitude after resetting are distinguishable among stimuli. SRs in tissue slice cultures reveal tissue-specific entrainment properties. These results demonstrate that SRs can be employed to unveil entrainment mechanisms with diverse stimuli in multiscale mammalian clocks.

DOI: https://doi.org/10.1038/s41467-023-38392-x