bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–04–02
39 papers selected by
Christian Frezza, Universität zu Köln
  1. NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner.
  2. Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade.
  3. The mitochondrial calcium uniporter complex-A play in five acts.
  4. Cytosolic and mitochondrial NADPH fluxes are independently regulated.
  5. Regulation of nucleotide metabolism in cancers and immune disorders.
  6. The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.
  7. FASN-deficiency induces a cytosol-to-mitochondria citrate flux to mitigate detachment-induced oxidative stress.
  8. Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5.
  9. Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.
  10. Evolution: 'Millefoglie' origin of mitochondrial cristae.
  11. Regulation of neuronal energy metabolism by calcium: Role of MCU and Aralar/malate-aspartate shuttle.
  12. Sustained IP3-linked Ca2+ signaling promotes progression of triple negative breast cancer cells by regulating fatty acid metabolism.
  13. Decoding the crosstalk between mevalonate metabolism and T cell function.
  14. Mitochondrial DNA Release in Innate Immune Signaling.
  15. Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer.
  16. A metabolic vulnerability of pancreatic cancer.
  17. Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.
  18. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.
  19. NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4.
  20. Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α.
  21. TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.
  22. Time-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.
  23. Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma.
  24. S-adenosyl-L-methionine supplementation alleviates the destructed intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.
  25. Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
  26. SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression.
  27. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.
  28. Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
  29. Reporting NADPH fluxes.
  30. Nucleotide metabolism: a pan-cancer metabolic dependency.
  31. Tryptophan metabolite improves PDAC response rates and survival.
  32. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.
  33. Nucleotide metabolism regulates human telomere length via telomerase activation.
  34. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion.
  35. Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.
  36. Large neutral amino acid levels tune perinatal neuronal excitability and survival.
  37. Early infiltration of innate immune cells to the liver depletes HNF4a and promotes extra-hepatic carcinogenesis.
  38. Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.
  39. An atlas of genetic scores to predict multi-omic traits.
  1. Proc Natl Acad Sci U S A. 2023 Apr 04. 120(14): e2220102120
    NAMPT-dependent NAD+ biosynthesis controls circadian metabolism in a tissue-specific manner.
    Astrid L Basse, Karen N Nielsen, Iuliia Karavaeva, Lars R Ingerslev, Tao Ma, Jesper F Havelund, Thomas S Nielsen, Mikkel Frost, Julia Peics, Emilie Dalbram, Morten Dall, Juleen R Zierath, Romain Barrès, Nils J Færgeman, Jonas T Treebak, Zachary Gerhart-Hines.
      Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD+ abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
    Keywords:  Brown adipose tissue; Circadian metabolism; Clock rhythm; NAD; Skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2220102120
  2. bioRxiv. 2023 Mar 23. pii: 2023.03.21.533091. [Epub ahead of print]
    Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade.
    Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, J L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.
      The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented 1 . While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages 1-,3 , whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology 4 we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5 , into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux without major effects on oxygen consumption, driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment in both mice and humans, promoting an anti- tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.
    DOI:  https://doi.org/10.1101/2023.03.21.533091
  3. Cell Calcium. 2023 Mar 24. pii: S0143-4160(23)00032-5. [Epub ahead of print]112 102720
    The mitochondrial calcium uniporter complex-A play in five acts.
    Agnese De Mario, Donato D'Angelo, Giuseppe Zanotti, Anna Raffaello, Cristina Mammucari.
      Mitochondrial Ca2+ (mitCa2+) uptake controls both intraorganellar and cytosolic functions. Within the organelle, [Ca2+] increases regulate the activity of tricarboxylic acid (TCA) cycle enzymes, thus sustaining oxidative metabolism and ATP production. Reactive oxygen species (ROS) are also generated as side products of oxygen consumption. At the same time, mitochondria act as buffers of cytosolic Ca2+ (cytCa2+) increases, thus regulating Ca2+-dependent cellular processes. In pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP) and the release of apoptotic cofactors. MitCa2+ uptake occurs in response of local [Ca2+] increases in sites of proximity between the endoplasmic reticulum (ER) and the mitochondria and is mediated by the mitochondrial Ca2+ uniporter (MCU), a highly selective channel of the inner mitochondrial membrane (IMM). Both channel and regulatory subunits form the MCU complex (MCUC). Cryogenic electron microscopy (Cryo-EM) and crystal structures revealed the correct assembly of MCUC and the function of critical residues for the regulation of Ca2+ conductance.
    DOI:  https://doi.org/10.1016/j.ceca.2023.102720
  4. Nat Chem Biol. 2023 Mar 27.
    Cytosolic and mitochondrial NADPH fluxes are independently regulated.
    Xiangfeng Niu, Ethan Stancliffe, Susan J Gelman, Lingjue Wang, Michaela Schwaiger-Haber, Joe L Rowles, Leah P Shriver, Gary J Patti.
      Although nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity.
    DOI:  https://doi.org/10.1038/s41589-023-01283-9
  5. Trends Cell Biol. 2023 Mar 24. pii: S0962-8924(23)00044-2. [Epub ahead of print]
    Regulation of nucleotide metabolism in cancers and immune disorders.
    Eunus S Ali, Issam Ben-Sahra.
      Nucleotides are the foundational elements of life. Proliferative cells acquire nutrients for energy production and the synthesis of macromolecules, including proteins, lipids, and nucleic acids. Nucleotides are continuously replenished through the activation of the nucleotide synthesis pathways. Despite the importance of nucleotides in cell physiology, there is still much to learn about how the purine and pyrimidine synthesis pathways are regulated in response to intracellular and exogenous signals. Over the past decade, evidence has emerged that several signaling pathways [Akt, mechanistic target of rapamycin complex I (mTORC1), RAS, TP53, and Hippo-Yes-associated protein (YAP) signaling] alter nucleotide synthesis activity and influence cell function. Here, we examine the mechanisms by which these signaling networks affect de novo nucleotide synthesis in mammalian cells. We also discuss how these molecular links can be targeted in diseases such as cancers and immune disorders.
    Keywords:  cancer metabolism; de novo purine and pyrimidine synthesis; immune disorders; metabolic vulnerability; nucleotide signaling; signaling pathways
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.003
  6. Cell Rep. 2023 Mar 31. pii: S2211-1247(23)00343-1. [Epub ahead of print]42(4): 112332
    The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.
    Pablo Rivera-Mejías, Álvaro Jesús Narbona-Pérez, Lidwina Hasberg, Lara Kroczek, Amir Bahat, Steffen Lawo, Kat Folz-Donahue, Anna-Lena Schumacher, Sofia Ahola, Fiona Carola Mayer, Patrick Giavalisco, Hendrik Nolte, Sergio Lavandero, Thomas Langer.
      The metabolic plasticity of mitochondria ensures cell development, differentiation, and survival. The peptidase OMA1 regulates mitochondrial morphology via OPA1 and stress signaling via DELE1 and orchestrates tumorigenesis and cell survival in a cell- and tissue-specific manner. Here, we use unbiased systems-based approaches to show that OMA1-dependent cell survival depends on metabolic cues. A metabolism-focused CRISPR screen combined with an integrated analysis of human gene expression data found that OMA1 protects against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote p53-dependent apoptosis of cells lacking OMA1. The protective effect of OMA1 does not depend on OMA1 activation or OMA1-mediated OPA1 and DELE1 processing. OMA1-deficient cells show reduced glycolysis and accumulate oxidative phosphorylation (OXPHOS) proteins upon DNA damage. OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. Thus, OMA1 dictates the balance between cell death and survival through the control of glucose metabolism, shedding light on its role in cancerogenesis.
    Keywords:  CP: Metabolism; DNA damage; OMA1; OXPHOS; glucose metabolism; mitochondria; nucleotides; p53
    DOI:  https://doi.org/10.1016/j.celrep.2023.112332
  7. bioRxiv. 2023 Mar 15. pii: 2023.03.14.532533. [Epub ahead of print]
    FASN-deficiency induces a cytosol-to-mitochondria citrate flux to mitigate detachment-induced oxidative stress.
    Wenting Dai, Zhichao Wang, Guan Wang, Qiong A Wang, Ralph DeBerardinis, Lei Jiang.
      Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl-CoA is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation under hypoxia. Here we show that reductive carboxylation also occurs in the absence of DNL in cells with defective FASN. In this state, reductive carboxylation was mainly catalyzed by isocitrate dehydrogenase-1 (IDH1) in the cytosol, but IDH1-generated citrate was not used for DNL. Metabolic flux analysis (MFA) revealed that FASN-deficiency induced a net cytosol-to-mitochondria citrate flux through citrate transport protein (CTP). A similar pathway was previously shown to mitigate detachment-induced mitochondrial reactive oxygen species (mtROS) in anchorage-independent tumor spheroids. We further demonstrate that FASN-deficient cells acquire resistance to oxidative stress in a CTP- and IDH1-dependent manner. Together with the reduced FASN activity in tumor spheroids, these data indicate that anchorage-independent malignant cells trade FASN-supported rapid growth for a cytosol-to-mitochondria citrate flux to gain redox capacity against detachment-induced oxidative stress.
    DOI:  https://doi.org/10.1101/2023.03.14.532533
  8. Metabolites. 2023 Feb 23. pii: 331. [Epub ahead of print]13(3):
    Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5.
    Fangfang Chen, Hanna Friederike Willenbockel, Thekla Cordes.
      The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the "multiple-hit theory" and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.
    Keywords:  NaCT; SLC13A5; TCA cycle; citrate metabolism; citrate transport; compartmentalization; mass spectrometry; metabolic niche; mitochondria; tracing
    DOI:  https://doi.org/10.3390/metabo13030331
  9. Nature. 2023 Mar 29.
    Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer.
    Min-Sik Lee, Courtney Dennis, Insia Naqvi, Lucas Dailey, Alireza Lorzadeh, George Ye, Tamara Zaytouni, Ashley Adler, Daniel S Hitchcock, Lin Lin, Megan T Hoffman, Aladdin M Bhuiyan, Jaimie L Barth, Miranda E Machacek, Mari Mino-Kenudson, Stephanie K Dougan, Unmesh Jadhav, Clary B Clish, Nada Y Kalaany.
      There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.
    DOI:  https://doi.org/10.1038/s41586-023-05891-2
  10. Curr Biol. 2023 Mar 27. pii: S0960-9822(23)00177-X. [Epub ahead of print]33(6): R219-R221
    Evolution: 'Millefoglie' origin of mitochondrial cristae.
    Paul A M Michels, Michael L Ginger.
      Striated intracytoplasmic membranes in alphaproteobacteria are often reminiscent of millefoglie pastries. A new study reveals a protein complex homologous to that responsible for mitochondrial cristae formation drives intracytoplasmic membrane formation, thereby establishing bacterial ancestry for the biogenesis of mitochondrial cristae.
    DOI:  https://doi.org/10.1016/j.cub.2023.02.037
  11. Biochim Biophys Acta Mol Cell Res. 2023 Mar 28. pii: S0167-4889(23)00039-3. [Epub ahead of print] 119468
    Regulation of neuronal energy metabolism by calcium: Role of MCU and Aralar/malate-aspartate shuttle.
    Araceli Del Arco, Luis González-Moreno, Irene Pérez-Liébana, Inés Juaristi, Paloma González-Sánchez, Laura Contreras, Beatriz Pardo, Jorgina Satrústegui.
      Calcium is a major regulator of cellular metabolism. Calcium controls mitochondrial respiration, and calcium signaling is used to meet cellular energetic demands through energy production in the organelle. Although it has been widely assumed that Ca2+-actions require its uptake by mitochondrial calcium uniporter (MCU), alternative pathways modulated by cytosolic Ca2+ have been recently proposed. Recent findings have indicated a role for cytosolic Ca2+ signals acting on mitochondrial NADH shuttles in the control of cellular metabolism in neurons using glucose as fuel. It has been demonstrated that AGC1/Aralar, the component of the malate/aspartate shuttle (MAS) regulated by cytosolic Ca2+, participates in the maintenance of basal respiration exerted through Ca2+-fluxes between ER and mitochondria, whereas mitochondrial Ca2+-uptake by MCU does not contribute. Aralar/MAS pathway, activated by small cytosolic Ca2+ signals, provides in fact substrates, redox equivalents and pyruvate, fueling respiration. Upon activation and increases in workload, neurons upregulate OxPhos, cytosolic pyruvate production and glycolysis, together with glucose uptake, in a Ca2+-dependent way, and part of this upregulation is via Ca2+ signaling. Both MCU and Aralar/MAS contribute to OxPhos upregulation, Aralar/MAS playing a major role, especially at small and submaximal workloads. Ca2+ activation of Aralar/MAS, by increasing cytosolic NAD+/NADH provides Ca2+-dependent increases in glycolysis and cytosolic pyruvate production priming respiration as a feed-forward mechanism in response to workload. Thus, except for glucose uptake, these processes are dependent on Aralar/MAS, whereas MCU is the relevant target for Ca2+ signaling when MAS is bypassed, by using pyruvate or β-hydroxybutyrate as substrates.
    Keywords:  Bioenergetic; Calcium signaling; Mitochondrial carriers; Neuronal activity; Neuronal metabolism; Redox shuttles; Respiration
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119468
  12. Front Cell Dev Biol. 2023 ;11 1071037
    Sustained IP3-linked Ca2+ signaling promotes progression of triple negative breast cancer cells by regulating fatty acid metabolism.
    Riccardo Filadi, Agnese De Mario, Matteo Audano, Patrizia Romani, Silvia Pedretti, Cesar Cardenas, Sirio Dupont, Cristina Mammucari, Nico Mitro, Paola Pizzo.
      Rewiring of mitochondrial metabolism has been described in different cancers as a key step for their progression. Calcium (Ca2+) signaling regulates mitochondrial function and is known to be altered in several malignancies, including triple negative breast cancer (TNBC). However, whether and how the alterations in Ca2+ signaling contribute to metabolic changes in TNBC has not been elucidated. Here, we found that TNBC cells display frequent, spontaneous inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ oscillations, which are sensed by mitochondria. By combining genetic, pharmacologic and metabolomics approaches, we associated this pathway with the regulation of fatty acid (FA) metabolism. Moreover, we demonstrated that these signaling routes promote TNBC cell migration in vitro, suggesting they might be explored to identify potential therapeutic targets.
    Keywords:  Ca2+; IP3; MCU; TNBC; acylcarnitine; breast cancer; fatty acids; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2023.1071037
  13. Immunol Rev. 2023 Mar 31.
    Decoding the crosstalk between mevalonate metabolism and T cell function.
    Kelly T Kennewick, Steven J Bensinger.
      The mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.
    Keywords:  T cells; cholesterol; isoprenoids; mevalonate pathway; statins
    DOI:  https://doi.org/10.1111/imr.13200
  14. Annu Rev Biochem. 2023 Mar 31.
    Mitochondrial DNA Release in Innate Immune Signaling.
    Laura E Newman, Gerald S Shadel.
      According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, and senescence and aging. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-032620-104401
  15. Acta Pharm Sin B. 2023 Mar;13(3): 1145-1163
    Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer.
    Juanjuan Feng, Zhengke Lian, Xinting Xia, Yue Lu, Kewen Hu, Yunpeng Zhang, Yanan Liu, Longmiao Hu, Kun Yuan, Zhenliang Sun, Xiufeng Pang.
      MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
    Keywords:  Carnitine palmitoyl transferase IA; Drug resistance; KRAS-mutant lung cancer; MEK inhibitors; Metabolic rewiring; Mitochondrial oxidative phosphorylation; Pyruvate dehydrogenase complex
    DOI:  https://doi.org/10.1016/j.apsb.2022.10.023
  16. Nature. 2023 Mar 29.
    A metabolic vulnerability of pancreatic cancer.
    Daniel J Puleston.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-00848-x
  17. Nutrients. 2023 Mar 21. pii: 1514. [Epub ahead of print]15(6):
    Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.
    Wan-Jing Chen, Su-Yu Huang, Yi-Wen Chen, Yi-Fang Liu, Rwei-Fen S Huang.
      Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.
    Keywords:  dietary folate deficiency; lactate metabolic disorders; lung cancer; mTORC1 signaling; metastasis; oncotargets
    DOI:  https://doi.org/10.3390/nu15061514
  18. Nature. 2023 Mar 29.
    STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.
    Jing Hu, Francisco J Sánchez-Rivera, Zhenghan Wang, Gabriela N Johnson, Yu-Jui Ho, Karuna Ganesh, Shigeaki Umeda, Siting Gan, Adriana M Mujal, Rebecca B Delconte, Jessica P Hampton, Huiyong Zhao, Sanjay Kottapalli, Elisa de Stanchina, Christine A Iacobuzio-Donahue, Dana Pe'er, Scott W Lowe, Joseph C Sun, Joan Massagué.
      Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.
    DOI:  https://doi.org/10.1038/s41586-023-05880-5
  19. Mol Oncol. 2023 Mar 28.
    NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4.
    Declan Whyte, George Skalka, Peter Walsh, Ania Wilczynska, Nikki R Paul, Claire Mitchell, Colin Nixon, William Clarke, Martin Bushell, Jennifer P Morton, Daniel J Murphy, Nathiya Muthalagu.
      The AMP-activated protein kinase (AMPK)-related kinase NUAK1 (NUAK family SNF1-like kinase 1) has emerged as a potential vulnerability in MYC-dependent cancer but the biological roles of NUAK1 in different settings are poorly characterised and the spectrum of cancer types that exhibit a requirement for NUAK1 is unknown. Unlike canonical oncogenes, NUAK1 is rarely mutated in cancer and appears to function as an obligate facilitator rather than a cancer driver per se. Although numerous groups have developed small-molecule NUAK inhibitors, the circumstances that would trigger their use and the unwanted toxicities that may arise as a consequence of on-target activity are thus undetermined. Reasoning that MYC is a key effector of RAS pathway signalling and the GTPase KRAS is almost uniformly mutated in pancreatic ductal adenocarcinoma (PDAC), we investigated whether this cancer type exhibits a functional requirement for NUAK1. Here, we show that high NUAK1 expression is associated with reduced overall survival in PDAC and that inhibition or depletion of NUAK1 suppresses growth of PDAC cells in culture. We identify a previously unknown role for NUAK1 in regulating accurate centrosome duplication and show that loss of NUAK1 triggers genomic instability. The latter activity is conserved in primary fibroblasts, raising the possibility of undesirable genotoxic effects of NUAK1 inhibition.
    Keywords:  Centrosome replication; GSK3β, MYPT1; NUAK1; PDAC; genomic instability
    DOI:  https://doi.org/10.1002/1878-0261.13425
  20. EMBO Rep. 2023 Mar 29. e56156
    Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α.
    Abigaelle Pelletier, Eric Nelius, Zheng Fan, Ekaterina Khatchatourova, Abdiel Alvarado-Diaz, Jingyi He, Ewelina Krzywinska, Michal Sobecki, Shunmugam Nagarajan, Yann Kerdiles, Joachim Fandrey, Dagmar Gotthardt, Veronika Sexl, Katrien de Bock, Christian Stockmann.
      Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining in situ metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1α as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD+ ) levels. The HIF-1α/NAD+ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steady-state conditions. In contrast, in activated NK cells under hypoxia, HIF-1α is required for glycolysis, and forced HIF-1α expression boosts glycolysis and NK cell performance in vitro and in vivo. Our data highlight two distinct pathways by which HIF-1α interferes with NK cell metabolism. While HIF-1α-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1α-dependent tryptophan/NAD+ metabolism.
    Keywords:  HIF; immunometabolism; natural killer cells; nicotinamide adenine dinucleotide; tryptophan
    DOI:  https://doi.org/10.15252/embr.202256156
  21. EMBO Mol Med. 2023 Mar 29. e16877
    TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.
    Chiara Di Malta, Angela Zampelli, Letizia Granieri, Claudia Vilardo, Rossella De Cegli, Laura Cinque, Edoardo Nusco, Salvatore Pece, Daniela Tosoni, Francesca Sanguedolce, Nicolina Cristina Sorrentino, Maria J Merino, Deborah Nielsen, Ramaprasad Srinivasan, Mark W Ball, Christopher J Ricketts, Cathy D Vocke, Martin Lang, Baktiar Karim, Luisa Lanfrancone, Laura S Schmidt, W Marston Linehan, Andrea Ballabio.
      Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.
    Keywords:  BHD; TFE3; TFEB; cysts; kidney cancer
    DOI:  https://doi.org/10.15252/emmm.202216877
  22. Nat Commun. 2023 Mar 27. 14(1): 1685
    Time-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.
    Quetzalcoatl Escalante-Covarrubias, Lucía Mendoza-Viveros, Mirna González-Suárez, Román Sitten-Olea, Laura A Velázquez-Villegas, Fernando Becerril-Pérez, Ignacio Pacheco-Bernal, Erick Carreño-Vázquez, Paola Mass-Sánchez, Marcia Bustamante-Zepeda, Ricardo Orozco-Solís, Lorena Aguilar-Arnal.
      The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD+. Increasing NAD+ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD+ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ treatment for diet-induced metabolic disease in mice. Increasing NAD+ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD+ immediately before the rest phase selectively compromised these responses. Remarkably, timed NAD+ adjusted circadian oscillations of the liver clock until completely inverting its oscillatory phase when increased just before the rest period, resulting in misaligned molecular and behavioral rhythms in male and female mice. Our findings unveil the time-of-day dependence of NAD+-based therapies and support a chronobiology-based approach.
    DOI:  https://doi.org/10.1038/s41467-023-37286-2
  23. Nat Commun. 2023 Mar 27. 14(1): 1681
    Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma.
    Yige Wu, Nadezhda V Terekhanova, Wagma Caravan, Nataly Naser Al Deen, Preet Lal, Siqi Chen, Chia-Kuei Mo, Song Cao, Yize Li, Alla Karpova, Ruiyang Liu, Yanyan Zhao, Andrew Shinkle, Ilya Strunilin, Cody Weimholt, Kazuhito Sato, Lijun Yao, Mamatha Serasanambati, Xiaolu Yang, Matthew Wyczalkowski, Houxiang Zhu, Daniel Cui Zhou, Reyka G Jayasinghe, Daniel Mendez, Michael C Wendl, David Clark, Chelsea Newton, Yijun Ruan, Melissa A Reimers, Russell K Pachynski, Chris Kinsinger, Scott Jewell, Daniel W Chan, Hui Zhang, Aadel A Chaudhuri, Milan G Chheda, Benjamin D Humphreys, Mehdi Mesri, Henry Rodriguez, James J Hsieh, Li Ding, Feng Chen.
      Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-023-37211-7
  24. Development. 2023 Mar 28. pii: dev.201135. [Epub ahead of print]
    S-adenosyl-L-methionine supplementation alleviates the destructed intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.
    Miao-Lin Li, Si-Yi Cao, Jia Qu, Lei Zhang, Qiang Gao, Xu Wang, Miao Yin, Ying Liu, Ming-Zhu Lei, Qun-Ying Lei.
      Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we define that Mat2a is essential for intestinal development and metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cells (IECs)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IECs apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspase-8/3 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in mice intestinal development and homeostasis.
    Keywords:   Mat2a ; Intestinal development; Intestinal homeostasis; Intestinal inflammation; SAM
    DOI:  https://doi.org/10.1242/dev.201135
  25. bioRxiv. 2023 Mar 21. pii: 2023.03.20.533505. [Epub ahead of print]
    Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
    Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu.
      Somatic mutations in non-malignant tissues accumulate with age and insult, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate mutations found in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to non-alcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7 , a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side-by-side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Bcl6, Tbx3, or Smyd2 resulted in protection against NASH. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.
    Highlights: Mosaic Mboat7 mutations that increase lipotoxicity lead to clonal disappearance in NASH. In vivo screening can identify genes that alter hepatocyte fitness in NASH. Mosaic Gpam mutations are positively selected due to reduced lipogenesis. In vivo screening of transcription factors and epifactors identified new therapeutic targets in NASH.
    DOI:  https://doi.org/10.1101/2023.03.20.533505
  26. Cell Metab. 2023 Mar 21. pii: S1550-4131(23)00082-7. [Epub ahead of print]
    SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression.
    Teresa Villanueva-Carmona, Lídia Cedó, Ana Madeira, Victòria Ceperuelo-Mallafré, M-Mar Rodríguez-Peña, Catalina Núñez-Roa, Elsa Maymó-Masip, Maria Repollés-de-Dalmau, Joan Badia, Noelia Keiran, Mercedes Mirasierra, Carolina Pimenta-Lopes, Joan Sabadell-Basallote, Ramón Bosch, Laura Caubet, Joan Carles Escolà-Gil, José-Manuel Fernández-Real, Nuria Vilarrasa, Francesc Ventura, Mario Vallejo, Joan Vendrell, Sonia Fernández-Veledo.
      Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.
    Keywords:  GPCR; SUCNR1; adipocyte; adipose tissue; circadian clock; leptin; metabolism; metabolite; obesity; succinate
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.004
  27. Cancer Cell. 2023 Mar 24. pii: S1535-6108(23)00082-X. [Epub ahead of print]
    Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.
    Joy A Pai, Matthew D Hellmann, Jennifer L Sauter, Marissa Mattar, Hira Rizvi, Hyung Jun Woo, Nisargbhai Shah, Evelyn M Nguyen, Fathema Z Uddin, Alvaro Quintanal-Villalonga, Joseph M Chan, Parvathy Manoj, Viola Allaj, Marina K Baine, Umesh K Bhanot, Mala Jain, Irina Linkov, Fanli Meng, David Brown, Jamie E Chaft, Andrew J Plodkowski, Mathieu Gigoux, Helen H Won, Triparna Sen, Daniel K Wells, Mark T A Donoghue, Elisa de Stanchina, Jedd D Wolchok, Brian Loomis, Taha Merghoub, Charles M Rudin, Andrew Chow, Ansuman T Satpathy.
      Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy.
    Keywords:  TCF-1 progenitor exhausted T cells; exhausted T cells; immune checkpoint blockade; lung cancer; single-cell RNA/TCR sequencing; tumor-specific T cells
    DOI:  https://doi.org/10.1016/j.ccell.2023.03.009
  28. bioRxiv. 2023 Mar 15. pii: 2023.03.14.532663. [Epub ahead of print]
    Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.
    Paul Renauer, Jonathan J Park, Meizhu Bai, Arianny Acosta, Won-Ho Lee, Guang Han Lin, Yueqi Zhang, Xiaoyun Dai, Guangchuan Wang, Youssef Errami, Terence Wu, Paul Clark, Lupeng Ye, Quanjun Yang, Sidi Chen.
      Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA -OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA -OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.
    Synopsis: The authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo .
    DOI:  https://doi.org/10.1101/2023.03.14.532663
  29. Nat Chem Biol. 2023 Mar 27.
    Reporting NADPH fluxes.
    Justin R Cross.
      
    DOI:  https://doi.org/10.1038/s41589-023-01298-2
  30. Nat Rev Cancer. 2023 Mar 27.
    Nucleotide metabolism: a pan-cancer metabolic dependency.
    Nicholas J Mullen, Pankaj K Singh.
      Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.
    DOI:  https://doi.org/10.1038/s41568-023-00557-7
  31. Nat Rev Cancer. 2023 Mar 27.
    Tryptophan metabolite improves PDAC response rates and survival.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41568-023-00566-6
  32. J Clin Invest. 2023 Mar 28. pii: e165019. [Epub ahead of print]
    CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.
    Charlotte Gehin, Museer A Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M Adeyemi, Erica H Gerkes, Alexander Pa Stegmann, Estrella López-Martín, Eva Bermejo-Sánchez, Beatriz Martínez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Gräfe, Ina Knerr, Eppie R Jones, Stefano Zamuner, Luciano A Abriata, Vidya Kunnathully, Brandon E Moeller, Anthony Vocat, Samuel Rommelaere, Jean-Philippe Bocquete, Evelyne Ruchti, Greta Limoni, Marine Van Campenhoudt, Samuel Bourgeat, Petra Henklein, Christian Gilissen, Bregje W van Bon, Rolph Pfundt, Marjolein H Willemsen, Jolanda H Schieving, Emanuela Leonardi, Fiorenza Soli, Alessandra Murgia, Hui Guo, Qiumeng Zhang, Kun Xia, Christina R Fagerberg, Christoph P Beier, Martin J Larsen, Irene Valenzuela, Paula Fernández-Álvarez, Shiyi Xiong, Robert Śmigiel, Vanesa López-González, Lluís Armengol, Manuela Morleo, Angelo Selicorni, Annalaura Torella, Moira Blyth, Nicola S Cooper, Valerie Wilson, Renske Oegema, Yvan Herenger, Aurore Garde, Ange-Line Bruel, Frederic Tran Mau-Them, Alexis Br Maddocks, Jennifer M Bain, Musadiq A Bhat, Gregory Costain, Peter Kannu, Ashish Marwaha, Neena L Champaigne, Michael J Friez, Ellen B Richardson, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Yask Gupta, Tze Y Lim, Simone Sanna-Cherchi, Bruno Lemaitre, Toshiyuki Yamaji, Kentaro Hanada, John E Burke, Ana Marija Jakšić, Brian D McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D'Angelo, Vincenzo A Gennarino.
      Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call CerTra syndrome. These findings uncover a central role for CERT autoregulation in the control of the sphingolipid biosynthetic flux, provide unexpected insight into the structural organisation of CERT, and suggest a possible therapeutic approach for CerTra syndrome patients.
    Keywords:  Cell Biology; Genetics; Lipid rafts; Neurodevelopment
    DOI:  https://doi.org/10.1172/JCI165019
  33. Nat Genet. 2023 Mar 30.
    Nucleotide metabolism regulates human telomere length via telomerase activation.
    Tracy M Bryan.
      
    DOI:  https://doi.org/10.1038/s41588-023-01359-1
  34. Nat Commun. 2023 Mar 30. 14(1): 1790
    The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion.
    Laura Onuchic, Valeria Padovano, Giorgia Schena, Vanathy Rajendran, Ke Dong, Xiaojian Shi, Raj Pandya, Victoria Rai, Nikolay P Gresko, Omair Ahmed, TuKiet T Lam, Weiwei Wang, Hongying Shen, Stefan Somlo, Michael J Caplan.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent potentially lethal monogenic disorder. Mutations in the PKD1 gene, which encodes polycystin-1 (PC1), account for approximately 78% of cases. PC1 is a large 462-kDa protein that undergoes cleavage in its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria. We show that transgenic expression of a protein corresponding to the final 200 amino acid (aa) residues of PC1 in two Pkd1-KO orthologous murine models of ADPKD suppresses cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). This interaction modulates tubular/cyst cell proliferation, the metabolic profile, mitochondrial function, and the redox state. Together, these results suggest that a short fragment of PC1 is sufficient to suppress cystic phenotype and open the door to the exploration of gene therapy strategies for ADPKD.
    DOI:  https://doi.org/10.1038/s41467-023-37449-1
  35. Nat Commun. 2023 Mar 27. 14(1): 1703
    Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.
    Themis Thoudam, Dipanjan Chanda, Jung Yi Lee, Min-Kyo Jung, Ibotombi Singh Sinam, Byung-Gyu Kim, Bo-Yoon Park, Woong Hee Kwon, Hyo-Jeong Kim, Myeongjin Kim, Chae Won Lim, Hoyul Lee, Yang Hoon Huh, Caroline A Miller, Romil Saxena, Nicholas J Skill, Nazmul Huda, Praveen Kusumanchi, Jing Ma, Zhihong Yang, Min-Ji Kim, Ji Young Mun, Robert A Harris, Jae-Han Jeon, Suthat Liangpunsakul, In-Kyu Lee.
      Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.
    DOI:  https://doi.org/10.1038/s41467-023-37214-4
  36. Cell. 2023 Mar 24. pii: S0092-8674(23)00215-5. [Epub ahead of print]
    Large neutral amino acid levels tune perinatal neuronal excitability and survival.
    Lisa S Knaus, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova, Mateja Smogavec, Lena A Schwarz, Sarah Gorkiewicz, Nicole Amberg, Florian M Pauler, Christian Knittl-Frank, Marianna Tassinari, Nuno Maulide, Thomas Rülicke, Jörg Menche, Simon Hippenmeyer, Gaia Novarino.
      Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.
    Keywords:  SLC7A5; autism; branched-chain amino acids; lipids; metabolism; microcephaly; neurodevelopment
    DOI:  https://doi.org/10.1016/j.cell.2023.02.037
  37. Cancer Discov. 2023 Mar 27. pii: CD-22-1062. [Epub ahead of print]
    Early infiltration of innate immune cells to the liver depletes HNF4a and promotes extra-hepatic carcinogenesis.
    Omer Goldman, Lital N Adler, Emma Hajaj, Tommaso Croese, Naama Darzi, Sivan Galai, Hila Tishler, Yarden Ariav, Dor Lavie, Liat Fellus-Alyagor, Roni Oren, Yuri Kuznetsov, Eyal David, Rami Jaschek, Chani Stossel, Oded Singer, Sergey Malitsky, Renana Barak, Rony Seger, Neta Erez, Ido Amit, Amos Tanay, Ann Saada, Talia Golan, Tamar Rubinek, Joo Sang Lee, Shay Ben-Shachar, Ido Wolf, Ayelet Erez.
      Multiple studies identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by the cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL-6-pSTAT3 immune-hepatocyte crosstalk cause the depletion of a master metabolic regulator, HNF4a, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4 levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macro-environment with diagnostic and potentially therapeutic implications for the host.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1062
  38. Sci Adv. 2023 Mar 31. 9(13): eabo3789
    Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.
    Rajendran Sanalkumar, Rui Dong, Lukuo Lee, Yu-Hang Xing, Sowmya Iyer, Igor Letovanec, Stefano La Rosa, Giovanna Finzi, Elettra Musolino, Roberto Papait, Ivan Chebib, G Petur Nielsen, Raffaele Renella, Gregory M Cote, Edwin Choy, Martin Aryee, Kimberly Stegmaier, Ivan Stamenkovic, Miguel N Rivera, Nicolò Riggi.
      Cell fate transitions observed in embryonic development involve changes in three-dimensional genomic organization that provide proper lineage specification. Whether similar events occur within tumor cells and contribute to cancer evolution remains largely unexplored. We modeled this process in the pediatric cancer Ewing sarcoma and investigated high-resolution looping and large-scale nuclear conformation changes associated with the oncogenic fusion protein EWS-FLI1. We show that chromatin interactions in tumor cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Conversely, EWS-FLI1 depletion led to the disassembly of these looping networks and a widespread nuclear reorganization through the establishment of new looping patterns and large-scale compartment configuration matching those observed in mesenchymal stem cells, a candidate Ewing sarcoma progenitor. Our data demonstrate that major architectural features of nuclear organization in cancer cells can depend on single oncogenes and are readily reversed to reestablish latent differentiation programs.
    DOI:  https://doi.org/10.1126/sciadv.abo3789
  39. Nature. 2023 Mar 29.
    An atlas of genetic scores to predict multi-omic traits.
    Yu Xu, Scott C Ritchie, Yujian Liang, Paul R H J Timmers, Maik Pietzner, Loïc Lannelongue, Samuel A Lambert, Usman A Tahir, Sebastian May-Wilson, Carles Foguet, Åsa Johansson, Praveen Surendran, Artika P Nath, Elodie Persyn, James E Peters, Clare Oliver-Williams, Shuliang Deng, Bram Prins, Jian'an Luan, Lorenzo Bomba, Nicole Soranzo, Emanuele Di Angelantonio, Nicola Pirastu, E Shyong Tai, Rob M van Dam, Helen Parkinson, Emma E Davenport, Dirk S Paul, Christopher Yau, Robert E Gerszten, Anders Mälarstig, John Danesh, Xueling Sim, Claudia Langenberg, James F Wilson, Adam S Butterworth, Michael Inouye.
      The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
    DOI:  https://doi.org/10.1038/s41586-023-05844-9
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