bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023‒11‒12
forty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
  2. ER-mitochondria contact sites in mitochondrial DNA dynamics, maintenance, and distribution.
  3. Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice.
  4. Fumarate hydratase as a metabolic regulator of immunity.
  5. Mitohormesis.
  6. Toxic UDPGA Accumulation Is a Metabolic Vulnerability of Cancer Cells.
  7. Glial metabolism checkpoints memory.
  8. Metabolic dependencies of metastasis-initiating cells in female breast cancer.
  9. Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients.
  10. Regulatory mechanisms of one-carbon metabolism enzymes.
  11. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
  12. Iron, Copper, and Selenium: Cancer's Thing for Redox Bling.
  13. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.
  14. Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators.
  15. Brown fat thermogenesis and branched-chain amino acids in metabolic disease.
  16. Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.
  17. Reductive stress in cancer: coming out of the shadows.
  18. Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization.
  19. The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.
  20. The power and potential of mitochondria transfer.
  21. Regenerating the heart by metabolically reprogramming the cardiomyocyte epigenome.
  22. Spatially resolved mapping of proteome turnover dynamics with subcellular precision.
  23. Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
  24. Hypoxia increases persulfide and polysulfide formation by AMP kinase dependent cystathionine gamma lyase phosphorylation.
  25. Tracing cancer evolution and heterogeneity using Hi-C.
  26. A Guide to Ferroptosis, the biological rust of cellular membranes.
  27. Transitional cell states sculpt tissue topology during lung regeneration.
  28. Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.
  29. Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
  30. Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.
  31. Microenvironmental stress drives tumor cell maladaptation and malignancy through regulation of mitochondrial and nuclear cytochrome c oxidase subunits.
  32. Mining cancer genomes for change-of-metabolic-function mutations.
  33. Molecular Crowding: Physiologic Sensing and Control.
  34. Mitochondrial AAA+ proteases.
  35. MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.
  36. O-GlcNAcylation determines the translational regulation and phase separation of YTHDF proteins.
  37. ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
  38. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
  39. Components of iron-Sulfur cluster assembly machineries are robust phylogenetic markers to trace the origin of mitochondria and plastids.
  40. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
  41. Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.
  1. Nat Metab. 2023 Nov 09.
    Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
    CRUK Rosetta Grand Challenge Consortium
      Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
    DOI:  https://doi.org/10.1038/s42255-023-00915-7
  2. Int J Biochem Cell Biol. 2023 Nov 04. pii: S1357-2725(23)00131-0. [Epub ahead of print] 106492
    ER-mitochondria contact sites in mitochondrial DNA dynamics, maintenance, and distribution.
    Hema Saranya Ilamathi, Marc Germain.
      Mitochondria are central cellular metabolic hubs. Their function requires proteins encoded by nuclear DNA, but also mitochondrial DNA (mtDNA) whose maintenance is essential for the proper function of the organelle. Defective mtDNA maintenance and distribution are associated with mitochondrial diseases. mtDNA is organized into nucleo-protein complexes called nucleoids that dynamically move along the mitochondrial network and interact with each other. mtDNA replication and nucleoid distribution is an active process regulated by the complex interplay of mitochondrial dynamics, endoplasmic reticulum (ER)-mitochondria contact sites, and cytoskeletal networks. For example, defects in mitochondrial fusion and fission or ER-mitochondria contact sites affect nucleoid maintenance and distribution. In this review, we discuss the process of nucleoid dynamics and the factors regulating nucleoid maintenance and distribution.
    Keywords:  ER sheets; ERMCS; mitochondria; mtDNA-nucleoid
    DOI:  https://doi.org/10.1016/j.biocel.2023.106492
  3. iScience. 2023 Nov 17. 26(11): 108196
    Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice.
    Nicole K H Yiew, Stanislaw Deja, Daniel Ferguson, Kevin Cho, Chaowapong Jarasvaraparn, Miriam Jacome-Sosa, Andrew J Lutkewitte, Sandip Mukherjee, Xiaorong Fu, Jason M Singer, Gary J Patti, Shawn C Burgess, Brian N Finck.
      The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.
    Keywords:  Cellular physiology; Human metabolism
    DOI:  https://doi.org/10.1016/j.isci.2023.108196
  4. Trends Cell Biol. 2023 Nov 06. pii: S0962-8924(23)00209-X. [Epub ahead of print]
    Fumarate hydratase as a metabolic regulator of immunity.
    Christian G Peace, Shane M O'Carroll, Luke A J O'Neill.
      Tricarboxylic acid (TCA) cycle metabolites have been implicated in modulating signalling pathways in immune cells. Notable examples include succinate and itaconate, which have pro- and anti-inflammatory roles, respectively. Recently, fumarate has emerged as having specific roles in macrophage activation, regulating the production of such cytokines as interleukin (IL)-10 and type I interferons (IFNs). Fumarate hydratase (FH) has been identified as a control point. Notably, FH loss in different models and cell types has been found to lead to DNA and RNA release from mitochondria which are sensed by cytosolic nucleic acid sensors including retinoic acid-inducible gene (RIG)-I, melanoma differentiation-associated protein (MDA)5, and cyclic GMP-AMP synthase (cGAS) to upregulate IFN-β production. These findings may have relevance in the pathogenesis and treatment of diseases associated with decreased FH levels such as systemic lupus erythematosus (SLE) or FH-deficient kidney cancer.
    Keywords:  immunometabolism; innate immunity; interferon; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.005
  5. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00380-7. [Epub ahead of print]35(11): 1872-1886
    Mitohormesis.
    Yu-Wei Cheng, Jie Liu, Toren Finkel.
      Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.011
  6. Cancer Discov. 2023 Nov 10. OF1
    Toxic UDPGA Accumulation Is a Metabolic Vulnerability of Cancer Cells.
      UXS1-mediated clearance of the sugar nucleotide UDPGA is a specific vulnerability of cancer cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-178
  7. Nat Metab. 2023 Nov 06.
    Glial metabolism checkpoints memory.
    L Felipe Barros.
      
    DOI:  https://doi.org/10.1038/s42255-023-00886-9
  8. Nat Commun. 2023 Nov 04. 14(1): 7076
    Metabolic dependencies of metastasis-initiating cells in female breast cancer.
    C Megan Young, Laurent Beziaud, Pierre Dessen, Angela Madurga Alonso, Albert Santamaria-Martínez, Joerg Huelsken.
      Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.
    DOI:  https://doi.org/10.1038/s41467-023-42748-8
  9. Nat Commun. 2023 Nov 08. 14(1): 7211
    Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients.
    Juraj Adamik, Paul V Munson, Deena M Maurer, Felix J Hartmann, Sean C Bendall, Rafael J Argüello, Lisa H Butterfield.
      Efficacy of cancer vaccines remains low and mechanistic understanding of antigen presenting cell function in cancer may improve vaccine design and outcomes. Here, we analyze the transcriptomic and immune-metabolic profiles of Dendritic Cells (DCs) from 35 subjects enrolled in a trial of DC vaccines in late-stage melanoma (NCT01622933). Multiple platforms identify metabolism as an important biomarker of DC function and patient overall survival (OS). We demonstrate multiple immune and metabolic gene expression pathway alterations, a functional decrease in OCR/OXPHOS and increase in ECAR/glycolysis in patient vaccines. To dissect molecular mechanisms, we utilize single cell SCENITH functional profiling and show patient clinical outcomes (OS) correlate with DC metabolic profile, and that metabolism is linked to immune phenotype. With single cell metabolic regulome profiling, we show that MCT1 (monocarboxylate transporter-1), a lactate transporter, is increased in patient DCs, as is glucose uptake and lactate secretion. Importantly, pre-vaccination circulating myeloid cells in patients used as precursors for DC vaccine generation are significantly skewed metabolically as are several DC subsets. Together, we demonstrate that the metabolic profile of DC is tightly associated with the immunostimulatory potential of DC vaccines from cancer patients. We link phenotypic and functional metabolic changes to immune signatures that correspond to suppressed DC differentiation.
    DOI:  https://doi.org/10.1038/s41467-023-42881-4
  10. J Biol Chem. 2023 Nov 08. pii: S0021-9258(23)02485-7. [Epub ahead of print] 105457
    Regulatory mechanisms of one-carbon metabolism enzymes.
    Boryana Petrova, Adam G Maynard, Peng Wang, Naama Kanarek.
      One-carbon metabolism is a central metabolic pathway critical for the biosynthesis of several amino acids, methyl group donors, and nucleotides. The pathway mostly relies on the transfer of a carbon unit from the amino acid serine, through the cofactor folate (in its several forms), and to the ultimate carbon acceptors that include nucleotides and methyl groups used for methylation of proteins, RNA, and DNA. Nucleotides are required for DNA replication, DNA repair, gene expression, and protein translation, through ribosomal RNA. Therefore, the one-carbon metabolism pathway is essential for cell growth and function in all cells, but is specifically important for rapidly proliferating cells. The regulation of one-carbon metabolism is a critical aspect of the normal and pathological function of the pathway, such as in cancer, where hijacking these regulatory mechanisms feeds an increased need for nucleotides. One-carbon metabolism is regulated at several levels: via gene expression, posttranslational modification, sub-cellular compartmentalization, allosteric inhibition, and feedback regulation. In this review we aim to inform the readers of relevant one-carbon metabolism regulation mechanisms, and to bring forward the need to further study this aspect of one-carbon metabolism. The review aims to integrate two major aspects of cancer metabolism - signaling downstream of nutrient sensing, and one-carbon metabolism, because while each of these is critical for the proliferation of cancerous cells, their integration is critical for comprehensive understating of cellular metabolism in transformed cells and can lead to clinically-relevant insights.
    Keywords:  allosteric inhibition; cancer metabolism; metabolic adaptation; metabolic compartmentalization; post-translational modifications; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.jbc.2023.105457
  11. Nat Aging. 2023 Nov 09.
    Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.
    Chrysa Nikopoulou, Niklas Kleinenkuhnen, Swati Parekh, Tonantzi Sandoval, Christoph Ziegenhain, Farina Schneider, Patrick Giavalisco, Kat-Folz Donahue, Anna Juliane Vesting, Marcel Kirchner, Mihaela Bozukova, Christian Vossen, Janine Altmüller, Thomas Wunderlich, Rickard Sandberg, Vangelis Kondylis, Achim Tresch, Peter Tessarz.
      Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.
    DOI:  https://doi.org/10.1038/s43587-023-00513-y
  12. Cold Spring Harb Perspect Med. 2023 Nov 06. pii: a041545. [Epub ahead of print]
    Iron, Copper, and Selenium: Cancer's Thing for Redox Bling.
    Erdem M Terzi, Richard Possemato.
      Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes.
    DOI:  https://doi.org/10.1101/cshperspect.a041545
  13. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00374-1. [Epub ahead of print]35(11): 1976-1995.e6
    Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.
    Cara L Green, Michaela E Trautman, Krittisak Chaiyakul, Raghav Jain, Yasmine H Alam, Reji Babygirija, Heidi H Pak, Michelle M Sonsalla, Mariah F Calubag, Chung-Yang Yeh, Anneliese Bleicher, Grace Novak, Teresa T Liu, Sarah Newman, Will A Ricke, Kristina A Matkowskyj, Irene M Ong, Cholsoon Jang, Judith Simcox, Dudley W Lamming.
      Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.
    Keywords:  aging; branched-chain amino acids; frailty; isoleucine; lifespan; metabolic health; mice; nutritional interventions; protein restriction
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.005
  14. JCI Insight. 2023 Nov 08. pii: e164694. [Epub ahead of print]8(21):
    Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators.
    Kostas C Nikolaou, Svenja Godbersen, Muthiah Manoharan, Stefan Wieland, Markus H Heim, Markus Stoffel.
      Nonalcoholic steatohepatitis (NASH) is a leading cause for chronic liver diseases. Current therapeutic options are limited due to an incomplete mechanistic understanding of how steatosis transitions to NASH. Here we show that the TRIM21 E3 ubiquitin ligase is induced by the synergistic actions of proinflammatory TNF-α and fatty acids in livers of humans and mice with NASH. TRIM21 ubiquitinates and degrades ChREBP, SREBP1, ACC1, and FASN, key regulators of de novo lipogenesis, and A1CF, an alternative splicing regulator of the high-activity ketohexokinase-C (KHK-C) isoform and rate-limiting enzyme of fructose metabolism. TRIM21-mediated degradation of these lipogenic activators improved steatosis and hyperglycemia as well as fructose and glucose tolerance. Our study identifies TRIM21 as a negative regulator of liver steatosis in NASH and provides mechanistic insights into an immunometabolic crosstalk that limits fatty acid synthesis and fructose metabolism during metabolic stress. Thus, enhancing this natural counteracting force of steatosis through inhibition of key lipogenic activators via TRIM21-mediated ubiquitination may provide a therapeutic opportunity to treat NASH.
    Keywords:  Diabetes; Hepatology
    DOI:  https://doi.org/10.1172/jci.insight.164694
  15. Endocr J. 2023 Nov 09.
    Brown fat thermogenesis and branched-chain amino acids in metabolic disease.
    Zachary Brown, Takeshi Yoneshiro.
      Since the 1960s, researchers have recognized an association between elevated plasma branched chain amino acids (BCAA) and metabolic disease, including type 2 diabetes mellitus and obesity, but the cause for it remained poorly understood. Recent advances in metabolomics, advanced imaging techniques, and genetic analyses over the past decade have enabled newfound insights into the mechanism of BCAA metabolic dysregulation across a variety of peripheral tissues and its impact on metabolic disease, suggesting a key role for brown adipose tissue (BAT) in determining BCAA metabolic homeostasis. Previous investigations into BAT have emphasized fatty acids and glucose as substrates for BAT thermogenesis. Here, we address the importance of BAT in systemic BCAA metabolism, driven via the newly identified mitochondrial BCAA carrier (MBC), as well as the impact of BAT-driven BCAA clearance on glucose homeostasis and metabolic disease. The newly identified MBC offers new therapeutic avenues by which BAT activity may be enhanced to improve metabolic and cardiovascular health, as well as other diseases in which increases of circulating BCAA may play a role in pathogenicity.
    Keywords:  Beige adipocytes; Branched-chain amino acids; Brown adipose tissue; Diabetes; Transporter
    DOI:  https://doi.org/10.1507/endocrj.EJ23-0205
  16. Cell Rep Med. 2023 Oct 31. pii: S2666-3791(23)00442-1. [Epub ahead of print] 101265
    Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.
    Hanneke L D M Willemen, Patrícia Silva Santos Ribeiro, Melissa Broeks, Nils Meijer, Sabine Versteeg, Annefien Tiggeler, Teun P de Boer, Jędrzej M Małecki, Pål Ø Falnes, Judith Jans, Niels Eijkelkamp.
      Pain often persists in patients with an inflammatory disease, even when inflammation has subsided. The molecular mechanisms leading to this failure in pain resolution and the transition to chronic pain are poorly understood. Mitochondrial dysfunction in sensory neurons links to chronic pain, but its role in resolution of inflammatory pain is unclear. Transient inflammation causes neuronal plasticity, called hyperalgesic priming, which impairs resolution of pain induced by a subsequent inflammatory stimulus. We identify that hyperalgesic priming in mice increases the expression of a mitochondrial protein (ATPSc-KMT) and causes mitochondrial and metabolic disturbances in sensory neurons. Inhibition of mitochondrial respiration, knockdown of ATPSCKMT expression, or supplementation of the affected metabolite is sufficient to restore resolution of inflammatory pain and prevents chronic pain development. Thus, inflammation-induced mitochondrial-dependent disturbances in sensory neurons predispose to a failure in resolution of inflammatory pain and development of chronic pain.
    Keywords:  chronic pain; inflammation; metabolism; mitochondria; redox; sensory neurons
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101265
  17. Trends Cancer. 2023 Nov 02. pii: S2405-8033(23)00213-3. [Epub ahead of print]
    Reductive stress in cancer: coming out of the shadows.
    Maolin Ge, Thales Papagiannakopoulos, Liron Bar-Peled.
      Redox imbalance is defined by disruption in oxidative and reductive pathways and has a central role in cancer initiation, development, and treatment. Although redox imbalance has traditionally been characterized by high levels of oxidative stress, emerging evidence suggests that an overly reductive environment is just as detrimental to cancer proliferation. Reductive stress is defined by heightened levels of antioxidants, including glutathione and elevated NADH, compared with oxidized NAD, which disrupts central biochemical pathways required for proliferation. With the advent of new technologies that measure and manipulate reductive stress, the sensors and drivers of this overlooked metabolic stress are beginning to be revealed. In certain genetically defined cancers, targeting reductive stress pathways may be an effective strategy. Redox-based pathways are gaining recognition as essential 'regulatory hubs,' and a broader understanding of reductive stress signaling promises not only to reveal new insights into metabolic homeostasis but also potentially to transform therapeutic options in cancer.
    Keywords:  KEAP1/NRF2; cancer metabolism; redox homeostasis; reductive stress
    DOI:  https://doi.org/10.1016/j.trecan.2023.10.002
  18. Nat Commun. 2023 Nov 09. 14(1): 7246
    Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization.
    Yangci Liu, Haoming Zhai, Helen Alemayehu, Jérôme Boulanger, Lee J Hopkins, Alicia C Borgeaud, Christina Heroven, Jonathan D Howe, Kendra E Leigh, Clare E Bryant, Yorgo Modis.
      NLRP3 induces caspase-1-dependent pyroptotic cell death to drive inflammation. Aberrant activity of NLRP3 occurs in many human diseases. NLRP3 activation induces ASC polymerization into a single, micron-scale perinuclear punctum. Higher resolution imaging of this signaling platform is needed to understand how it induces pyroptosis. Here, we apply correlative cryo-light microscopy and cryo-electron tomography to visualize ASC/caspase-1 in NLRP3-activated cells. The puncta are composed of branched ASC filaments, with a tubular core formed by the pyrin domain. Ribosomes and Golgi-like or endosomal vesicles permeate the filament network, consistent with roles for these organelles in NLRP3 activation. Mitochondria are not associated with ASC but have outer-membrane discontinuities the same size as gasdermin D pores, consistent with our data showing gasdermin D associates with mitochondria and contributes to mitochondrial depolarization.
    DOI:  https://doi.org/10.1038/s41467-023-43180-8
  19. J Neurochem. 2023 Nov 06.
    The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.
    Elisa M York, Anne Miller, Sylwia A Stopka, Juan Ramón Martínez-François, Md Amin Hossain, Gerard Baquer, Michael S Regan, Nathalie Y R Agar, Gary Yellen.
      The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI-MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β-hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition.
    Keywords:  brain metabolism; glucose metabolism; ketone body metabolism; lactate metabolism; mass spectrometry imaging; stable isotope tracing
    DOI:  https://doi.org/10.1111/jnc.16004
  20. Nature. 2023 Nov;623(7986): 283-291
    The power and potential of mitochondria transfer.
    Nicholas Borcherding, Jonathan R Brestoff.
      Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, with vertical inheritance of mitochondria and the mitochondrial DNA genome from parent to daughter cells. However, an emerging body of literature indicates that some cell types export their mitochondria for delivery to developmentally unrelated cell types, a process called intercellular mitochondria transfer. In this Review, we describe the mechanisms by which mitochondria are transferred between cells and discuss how intercellular mitochondria transfer regulates the physiology and function of various organ systems in health and disease. In particular, we discuss the role of mitochondria transfer in regulating cellular metabolism, cancer, the immune system, maintenance of tissue homeostasis, mitochondrial quality control, wound healing and adipose tissue function. We also highlight the potential of targeting intercellular mitochondria transfer as a therapeutic strategy to treat human diseases and augment cellular therapies.
    DOI:  https://doi.org/10.1038/s41586-023-06537-z
  21. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00376-5. [Epub ahead of print]35(11): 1849-1851
    Regenerating the heart by metabolically reprogramming the cardiomyocyte epigenome.
    Xiaoqiang Tang.
      In mammal adolescence, cardiomyocytes rapidly exit the cell cycle, and heart regeneration in adults is limited after cardiac injury. Recent work by Li et al. in Nature revealed that inhibition of fatty acid oxidation can rewire cell metabolism and lead to epigenetic reprogramming of cardiomyocytes to an immature state that facilitates cardiomyocyte cell-cycle reentry and heart regeneration in adult animals.
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.007
  22. Nat Commun. 2023 Nov 08. 14(1): 7217
    Spatially resolved mapping of proteome turnover dynamics with subcellular precision.
    Feng Yuan, Yi Li, Xinyue Zhou, Peiyuan Meng, Peng Zou.
      Cellular activities are commonly associated with dynamic proteomic changes at the subcellular level. Although several techniques are available to quantify whole-cell protein turnover dynamics, such measurements often lack sufficient spatial resolution at the subcellular level. Herein, we report the development of prox-SILAC method that combines proximity-dependent protein labeling (APEX2/HRP) with metabolic incorporation of stable isotopes (pulse-SILAC) to map newly synthesized proteins with subcellular spatial resolution. We apply prox-SILAC to investigate proteome dynamics in the mitochondrial matrix and the endoplasmic reticulum (ER) lumen. Our analysis reveals a highly heterogeneous distribution in protein turnover dynamics within macromolecular machineries such as the mitochondrial ribosome and respiratory complexes I-V, thus shedding light on their mechanism of hierarchical assembly. Furthermore, we investigate the dynamic changes of ER proteome when cells are challenged with stress or undergoing stimulated differentiation, identifying subsets of proteins with unique patterns of turnover dynamics, which may play key regulatory roles in alleviating stress or promoting differentiation. We envision that prox-SILAC could be broadly applied to profile protein turnover at various subcellular compartments, under both physiological and pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-023-42861-8
  23. EMBO J. 2023 Nov 07. e114054
    Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
    Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Daniel Milshteyn, Guy Perkins, Keun-Young Kim, H Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark H Ellisman, Padmini Rangamani, Itay Budin.
      Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.
    Keywords:  cardiolipin; cristae; lipids; mechanics; mitochondria
    DOI:  https://doi.org/10.15252/embj.2023114054
  24. Redox Biol. 2023 Oct 30. pii: S2213-2317(23)00350-6. [Epub ahead of print]68 102949
    Hypoxia increases persulfide and polysulfide formation by AMP kinase dependent cystathionine gamma lyase phosphorylation.
    Shafiul Alam, Sibile Pardue, Xinggui Shen, John D Glawe, Takashi Yagi, Mohammad Alfrad Nobel Bhuiyan, Rakesh P Patel, Paari S Dominic, Chiranjiv S Virk, Md Shenuarin Bhuiyan, A Wayne Orr, Chad Petit, Gopi K Kolluru, Christopher G Kevil.
      Hydropersulfide and hydropolysulfide metabolites are increasingly important reactive sulfur species (RSS) regulating numerous cellular redox dependent functions. Intracellular production of these species is known to occur through RSS interactions or through translational mechanisms involving cysteinyl t-RNA synthetases. However, regulation of these species under cell stress conditions, such as hypoxia, that are known to modulate RSS remain poorly understood. Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer. Importantly, both cellular hypoxia and tissue ischemia result in AMP Kinase dependent CSE phosphorylation that regulates blood flow in ischemic tissues. Our findings reveal hypoxia molecular signaling pathways regulating CSE dependent persulfide and polysulfide production impacting tissue and cellular response to stress.
    Keywords:  AMP kinase; Cystathionine gamma lyase; Ischemia; Molecular modeling; Persulfide; Phosphorylation; Polysulfide
    DOI:  https://doi.org/10.1016/j.redox.2023.102949
  25. Nat Commun. 2023 Nov 06. 14(1): 7111
    Tracing cancer evolution and heterogeneity using Hi-C.
    Dan Daniel Erdmann-Pham, Sanjit Singh Batra, Timothy K Turkalo, James Durbin, Marco Blanchette, Iwei Yeh, Hunter Shain, Boris C Bastian, Yun S Song, Daniel S Rokhsar, Dirk Hockemeyer.
      Chromosomal rearrangements can initiate and drive cancer progression, yet it has been challenging to evaluate their impact, especially in genetically heterogeneous solid cancers. To address this problem we developed HiDENSEC, a new computational framework for analyzing chromatin conformation capture in heterogeneous samples that can infer somatic copy number alterations, characterize large-scale chromosomal rearrangements, and estimate cancer cell fractions. After validating HiDENSEC with in silico and in vitro controls, we used it to characterize chromosome-scale evolution during melanoma progression in formalin-fixed tumor samples from three patients. The resulting comprehensive annotation of the genomic events includes copy number neutral translocations that disrupt tumor suppressor genes such as NF1, whole chromosome arm exchanges that result in loss of CDKN2A, and whole-arm copy-number neutral loss of homozygosity involving PTEN. These findings show that large-scale chromosomal rearrangements occur throughout cancer evolution and that characterizing these events yields insights into drivers of melanoma progression.
    DOI:  https://doi.org/10.1038/s41467-023-42651-2
  26. FEBS J. 2023 Nov 07.
    A Guide to Ferroptosis, the biological rust of cellular membranes.
    Geraldine Veeckmans, Emily Van San, Tom Vanden Berghe.
      Unprotected iron can rust due to oxygen exposure. Similarly, in our body, oxidative stress can kill cells in an iron-dependent manner, which can give rise to devastating diseases. This type of cell death is referred to as ferroptosis. Generally, ferroptosis is defined as an iron-catalyzed form of regulated necrosis that occurs through excessive peroxidation of polyunsaturated fatty acids within cellular membranes. This review summarizes how ferroptosis is executed by a rather primitive biochemical process, under tight regulation of lipid, iron, and redox metabolic processes. An overview is given of major classes of ferroptosis inducers and inhibitors, and how to detect ferroptosis. Finally, its detrimental role in disease is briefly discussed.
    Keywords:  FSP1; Ferroptosis; GPX4; iron; lipid; lipid peroxidation; metabolism; radical trapping antioxidant; redox
    DOI:  https://doi.org/10.1111/febs.16993
  27. Cell Stem Cell. 2023 Nov 02. pii: S1934-5909(23)00363-6. [Epub ahead of print]30(11): 1486-1502.e9
    Transitional cell states sculpt tissue topology during lung regeneration.
    Arvind Konkimalla, Satoshi Konishi, Lauren Macadlo, Yoshihiko Kobayashi, Zachary J Farino, Naoya Miyashita, Léa El Haddad, Jeremy Morowitz, Christina E Barkauskas, Pankaj Agarwal, Tomokazu Souma, Mai K ElMallah, Aleksandra Tata, Purushothama Rao Tata.
      Organ regeneration requires dynamic cell interactions to reestablish cell numbers and tissue architecture. While we know the identity of progenitor cells that replace lost tissue, the transient states they give rise to and their role in repair remain elusive. Here, using multiple injury models, we find that alveolar fibroblasts acquire distinct states marked by Sfrp1 and Runx1 that influence tissue remodeling and reorganization. Unexpectedly, ablation of alveolar epithelial type-1 (AT1) cells alone is sufficient to induce tissue remodeling and transitional states. Integrated scRNA-seq followed by genetic interrogation reveals RUNX1 is a key driver of fibroblast states. Importantly, the ectopic induction or accumulation of epithelial transitional states induce rapid formation of transient alveolar fibroblasts, leading to organ-wide fibrosis. Conversely, the elimination of epithelial or fibroblast transitional states or RUNX1 loss, leads to tissue simplification resembling emphysema. This work uncovered a key role for transitional states in orchestrating tissue topologies during regeneration.
    Keywords:  RUNX1; alveolar epithelial cells; alveolar fibroblasts; emphysema; extracellular matrix organization; fibrosis; lung regeneration; remodeling; tissue topology; transitional states
    DOI:  https://doi.org/10.1016/j.stem.2023.10.001
  28. Cell Rep Med. 2023 Oct 31. pii: S2666-3791(23)00441-X. [Epub ahead of print] 101264
    Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.
    Tao Xing, Li Li, Yiran Chen, Gaoda Ju, Guilan Li, Xiaoyun Zhu, Yubo Ren, Jing Zhao, Zhilei Cheng, Yan Li, Da Xu, Jun Liang.
      ARID1A is among the most commonly mutated tumor suppressor genes in hepatocellular carcinoma (HCC). In this study, we conduct a CRISPR-Cas9 synthetic lethality screen using ARID1A-deficient HCC cells to identify approaches to treat HCC patients harboring ARID1A deficiency. This strategy reveals that the survival of these ARID1A-deficient HCC cells is highly dependent on genes related to the tricarboxylic acid (TCA) cycle. Mechanistically, ARID1A loss represses expression of key glycolysis-related gene PKM, shifting cellular glucose metabolism from aerobic glycolysis to dependence on the TCA cycle and oxidative phosphorylation. Cuproptosis is a recently defined form of copper-induced cell death reported to directly target the TCA cycle. Here, we find that ARID1A-deficient HCC cells and xenograft tumors are highly sensitive to copper treatment. Together, these results offer evidence of the synthetic lethality between ARID1A deficiency and mitochondrial respiration impairment, suggesting that copper treatment constitutes a promising therapeutic strategy for selectively targeting ARID1A-deficient HCC.
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101264
  29. EMBO Rep. 2023 Nov 06. e57339
    Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
    Shuchen Liu, Alberto Benito-Martin, Fanny A Pelissier Vatter, Sarah Z Hanif, Catherine Liu, Priya Bhardwaj, Praveen Sethupathy, Alaa R Farghli, Phoebe Piloco, Paul Paik, Malik Mushannen, Xue Dong, David M Otterburn, Leslie Cohen, Rohan Bareja, Jan Krumsiek, Leona Cohen-Gould, Samuel Calto, Jason A Spector, Olivier Elemento, David C Lyden, Kristy A Brown.
      Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.
    Keywords:  breast cancer; extracellular vesicles; mitochondrial respiration; obesity; proliferation
    DOI:  https://doi.org/10.15252/embr.202357339
  30. Nat Commun. 2023 Nov 08. 14(1): 6764
    Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.
    Igor Dolgalev, Hua Zhou, Nina Murrell, Hortense Le, Theodore Sakellaropoulos, Nicolas Coudray, Kelsey Zhu, Varshini Vasudevaraja, Anna Yeaton, Chandra Goparaju, Yonghua Li, Imran Sulaiman, Jun-Chieh J Tsay, Peter Meyn, Hussein Mohamed, Iris Sydney, Tomoe Shiomi, Sitharam Ramaswami, Navneet Narula, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw A Smolen, Wei-Yi Cheng, James Cai, Salman Punekar, Vamsidhar Velcheti, Daniel H Sterman, J T Poirier, Ben Neel, Kwok-Kin Wong, Luis Chiriboga, Adriana Heguy, Thales Papagiannakopoulos, Bettina Nadorp, Matija Snuderl, Leopoldo N Segal, Andre L Moreira, Harvey I Pass, Aristotelis Tsirigos.
      Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
    DOI:  https://doi.org/10.1038/s41467-023-42327-x
  31. Am J Physiol Cell Physiol. 2023 Nov 06.
    Microenvironmental stress drives tumor cell maladaptation and malignancy through regulation of mitochondrial and nuclear cytochrome c oxidase subunits.
    Davide Gnocchi, Dragana Nikolic, Francesca Castellaneta, Rita R Paparella, Carlo Sabbà, Antonio Mazzocca.
      After decades of focus on molecular genetics in cancer research, the role of metabolic and environmental factors is being reassessed. Here, we investigated the role of microenvironment in the promotion of malignant behavior in tumor cells with a different reliance on oxidative phosphorylation (OXPHOS) versus lactic acid fermentation/Warburg effect. To this end, we evaluated the effects of microenvironmental challenges (hypoxia, acidity, and high glucose) on the expression of mitochondrial-encoded cytochrome c oxidase 1 (COX I) and two nuclear-encoded isoforms 4 (COX IV-1 and COX IV-2). We have shown that tumor cells with an "OXPHOS phenotype" respond to hypoxia by upregulating COX IV-1, whereas cells that rely on lactic acid fermentation maximized COX IV-2 expression. Acidity upregulates COX IV-2 regardless of the metabolic state of the cell, whereas high glucose stimulates the expression of COX I and COX IV-1, with a stronger effect in fermenting cells. Our results uncover that "energy phenotype" of tumor cells drives their adaptive response to microenvironment stress.
    Keywords:  Tumor microenvironment; Warburg phenotype; cytochrome c oxidase subunits; malignancy; mitochondria
    DOI:  https://doi.org/10.1152/ajpcell.00508.2023
  32. Commun Biol. 2023 Nov 10. 6(1): 1143
    Mining cancer genomes for change-of-metabolic-function mutations.
    Kevin J Tu, Bill H Diplas, Joshua A Regal, Matthew S Waitkus, Christopher J Pirozzi, Zachary J Reitman.
      Enzymes with novel functions are needed to enable new organic synthesis techniques. Drawing inspiration from gain-of-function cancer mutations that functionally alter proteins and affect cellular metabolism, we developed METIS (Mutated Enzymes from Tumors In silico Screen). METIS identifies metabolism-altering cancer mutations using mutation recurrence rates and protein structure. We used METIS to screen 298,517 cancer mutations and identify 48 candidate mutations, including those previously identified to alter enzymatic function. Unbiased metabolomic profiling of cells exogenously expressing a candidate mutant (OGDHLp.A400T) supports an altered phenotype that boosts in vitro production of xanthosine, a pharmacologically useful chemical that is currently produced using unsustainable, water-intensive methods. We then applied METIS to 49 million cancer mutations, yielding a refined set of candidates that may impart novel enzymatic functions or contribute to tumor progression. Thus, METIS can be used to identify and catalog potentially-useful cancer mutations for green chemistry and therapeutic applications.
    DOI:  https://doi.org/10.1038/s42003-023-05475-w
  33. Annu Rev Physiol. 2023 Nov 06.
    Molecular Crowding: Physiologic Sensing and Control.
    Arohan R Subramanya, Cary R Boyd-Shiwarski.
      The cytoplasm is densely packed with molecules that contribute to its nonideal behavior. Cytosolic crowding influences chemical reaction rates, intracellular water mobility, and macromolecular complex formation. Overcrowding is potentially catastrophic; to counteract this problem, cells have evolved acute and chronic homeostatic mechanisms that optimize cellular crowdedness. Here, we provide a physiology-focused overview of molecular crowding, highlighting contemporary advances in our understanding of its sensing and control. Long hypothesized as a form of crowding-induced microcompartmentation, phase separation allows cells to detect and respond to intracellular crowding through the action of biomolecular condensates, as indicated by recent studies. Growing evidence indicates that crowding is closely tied to cell size and fluid volume, homeostatic responses to physical compression and desiccation, tissue architecture, circadian rhythm, aging, transepithelial transport, and total body electrolyte and water balance. Thus, molecular crowding is a fundamental physiologic parameter that impacts diverse functions extending from molecule to organism. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-physiol-042222-025920
  34. Enzymes. 2023 ;pii: S1874-6047(23)00028-8. [Epub ahead of print]54 205-220
    Mitochondrial AAA+ proteases.
    Yuichi Matsushima.
      Mitochondria are multifunctional organelles that play a central role in a wide range of life-sustaining tasks in eukaryotic cells, including adenosine triphosphate (ATP) production, calcium storage and coenzyme generation pathways such as iron-sulfur cluster biosynthesis. The wide range of mitochondrial functions is carried out by a diverse array of proteins comprising approximately 1500 proteins or polypeptides. Degradation of these proteins is mainly performed by four AAA+ proteases localized in mitochondria. These AAA+ proteases play a quality control role in degrading damaged or misfolded proteins and perform various other functions. This chapter describes previously identified roles for these AAA+ proteases that are localized in the mitochondria of animal cells.
    Keywords:  AAA+ protease; ClpXP; Lon; Mitochondria; i-AAA; m-AAA
    DOI:  https://doi.org/10.1016/bs.enz.2023.09.002
  35. Nat Cell Biol. 2023 Nov 09.
    MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.
    Alicia Llorente, María Teresa Blasco, Irene Espuny, Marc Guiu, Cecilia Ballaré, Enrique Blanco, Adrià Caballé, Anna Bellmunt, Fernando Salvador, Andrea Morales, Marc Nuñez, Guillem Loren, Francesca Imbastari, Marta Fidalgo, Cristina Figueras-Puig, Patrizia Gibler, Mariona Graupera, Freddy Monteiro, Antoni Riera, Ingunn Holen, Alexandra Avgustinova, Luciano Di Croce, Roger R Gomis.
      MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.
    DOI:  https://doi.org/10.1038/s41556-023-01281-y
  36. Nat Cell Biol. 2023 Nov;25(11): 1676-1690
    O-GlcNAcylation determines the translational regulation and phase separation of YTHDF proteins.
    Yulin Chen, Ruixi Wan, Zhongyu Zou, Lihui Lao, Guojian Shao, Yingying Zheng, Ling Tang, Ying Yuan, Yun Ge, Chuan He, Shixian Lin.
      N6-methyladenosine (m6A) is the most abundant internal mRNA nucleotide modification in mammals, regulating critical aspects of cell physiology and differentiation. The YTHDF proteins are the primary readers of m6A modifications and exert physiological functions of m6A in the cytosol. Elucidating the regulatory mechanisms of YTHDF proteins is critical to understanding m6A biology. Here we report a mechanism that protein post-translational modifications control the biological functions of the YTHDF proteins. We find that YTHDF1 and YTHDF3, but not YTHDF2, carry high levels of nutrient-sensing O-GlcNAc modifications. O-GlcNAcylation attenuates the translation-promoting function of YTHDF1 and YTHDF3 by blocking their interactions with proteins associated with mRNA translation. We further demonstrate that O-GlcNAc modifications on YTHDF1 and YTHDF3 regulate the assembly, stability and disassembly of stress granules to enable better recovery from stress. Therefore, our results discover an important regulatory pathway of YTHDF functions, adding an additional layer of complexity to the post-transcriptional regulation function of mRNA m6A.
    DOI:  https://doi.org/10.1038/s41556-023-01258-x
  37. Life Sci Alliance. 2024 Jan;pii: e202302335. [Epub ahead of print]7(1):
    ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
    Alexandre Janer, Jordan L Morris, Michiel Krols, Hana Antonicka, Mari J Aaltonen, Zhen-Yuan Lin, Hanish Anand, Anne-Claude Gingras, Julien Prudent, Eric A Shoubridge.
      Mitochondria interact with the ER at structurally and functionally specialized membrane contact sites known as mitochondria-ER contact sites (MERCs). Combining proximity labelling (BioID), co-immunoprecipitation, confocal microscopy and subcellular fractionation, we found that the ER resident SMP-domain protein ESYT1 was enriched at MERCs, where it forms a complex with the outer mitochondrial membrane protein SYNJ2BP. BioID analyses using ER-targeted, outer mitochondrial membrane-targeted, and MERC-targeted baits, confirmed the presence of this complex at MERCs and the specificity of the interaction. Deletion of ESYT1 or SYNJ2BP reduced the number and length of MERCs. Loss of the ESYT1-SYNJ2BP complex impaired ER to mitochondria calcium flux and provoked a significant alteration of the mitochondrial lipidome, most prominently a reduction of cardiolipins and phosphatidylethanolamines. Both phenotypes were rescued by reexpression of WT ESYT1 and an artificial mitochondria-ER tether. Together, these results reveal a novel function for ESYT1 in mitochondrial and cellular homeostasis through its role in the regulation of MERCs.
    DOI:  https://doi.org/10.26508/lsa.202302335
  38. Immunity. 2023 Oct 31. pii: S1074-7613(23)00444-2. [Epub ahead of print]
    Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
    Rui Miao, Cong Jiang, Winston Y Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G Liang, Junbing Zhang, Charles L Evavold, Iva Hafner-Bratkovič, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C Kagan, Richard N Kitsis, Peng Zhang, Xing Liu, Judy Lieberman.
      Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.
    Keywords:  CRLS1; GSDMD; IL-1; PLSCR3; cardiolipin; mitochondria; pyroptosis
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.004
  39. PLoS Biol. 2023 Nov;21(11): e3002374
    Components of iron-Sulfur cluster assembly machineries are robust phylogenetic markers to trace the origin of mitochondria and plastids.
    Pierre Simon Garcia, Frédéric Barras, Simonetta Gribaldo.
      Establishing the origin of mitochondria and plastids is key to understand 2 founding events in the origin and early evolution of eukaryotes. Recent advances in the exploration of microbial diversity and in phylogenomics approaches have indicated a deep origin of mitochondria and plastids during the diversification of Alphaproteobacteria and Cyanobacteria, respectively. Here, we strongly support these placements by analyzing the machineries for assembly of iron-sulfur ([Fe-S]) clusters, an essential function in eukaryotic cells that is carried out in mitochondria by the ISC machinery and in plastids by the SUF machinery. We assessed the taxonomic distribution of ISC and SUF in representatives of major eukaryotic supergroups and analyzed the phylogenetic relationships with their prokaryotic homologues. Concatenation datasets of core ISC proteins show an early branching of mitochondria within Alphaproteobacteria, right after the emergence of Magnetococcales. Similar analyses with the SUF machinery place primary plastids as sister to Gloeomargarita within Cyanobacteria. Our results add to the growing evidence of an early emergence of primary organelles and show that the analysis of essential machineries of endosymbiotic origin provide a robust signal to resolve ancient and fundamental steps in eukaryotic evolution.
    DOI:  https://doi.org/10.1371/journal.pbio.3002374
  40. JCI Insight. 2023 Nov 08. pii: e167874. [Epub ahead of print]8(21):
    SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
    Sha-Sha Hu, Yue Han, Tian-Yuan Tan, Hui Chen, Jia-Wen Gao, Lan Wang, Min-Hui Yang, Li Zhao, Yi-Qing Wang, Yan-Qing Ding, Shuang Wang.
      Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
    Keywords:  Amino acid metabolism; Colorectal cancer; Drug therapy; Gastroenterology; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.167874
  41. Cancer Discov. 2023 Nov 07.
    Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.
    Zhuxuan Li, Xueqian Zhuang, Chun-Hao Pan, Yan Yan, Rohit Thummalapalli, Jill Hallin, Stefan R Torborg, Anupriya Singhal, Jason C Chang, Eusebio Manchado, Lukas E Dow, Rona Yaeger, James G Christensen, Scott W Lowe, Charles M Rudin, Simon Joost, Tuomas Tammela.
      Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0289
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