bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023‒09‒03
thirty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
  2. Spotlight on GOT2 in Cancer Metabolism.
  3. The malate-aspartate shuttle is important for de novo serine biosynthesis.
  4. MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.
  5. A yeast vacuolar pH 'heartbeat' coordinates amino acid metabolism and the cell cycle.
  6. The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.
  7. Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
  8. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
  9. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
  10. Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
  11. Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
  12. Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.
  13. Interferon signaling restrains renal cell carcinoma heterogeneity.
  14. Metabolic programs of T cell tissue residency empower tumour immunity.
  15. Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells.
  16. Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
  17. Unleashing ferroptosis for cancer therapy with warfarin.
  18. T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
  19. Lysosomal glucose sensing and glycophagy in metabolism.
  20. Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
  21. Measuring the Metabolic State of Tissue-Resident Macrophages via SCENITH.
  22. Metabolic partitioning in the brain and its hijacking by glioblastoma.
  23. Identification of an alternative triglyceride biosynthesis pathway.
  24. Mitochondrial phospholipid metabolism in health and disease.
  25. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
  26. Machine learning of cellular metabolic rewiring.
  27. Formate promotes invasion and metastasis in reliance on lipid metabolism.
  28. Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.
  29. Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
  30. Proteomic analysis of murine kidney proximal tubule sub-segment derived cell lines reveals preferences in mitochondrial pathway activity.
  31. CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.
  32. Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission.
  33. Astrocytic GABA in LHA is an obesity 'thermostat'.
  34. Previously unknown pathway for lipid biosynthesis discovered.
  35. Alternative oxidase causes cell type- and tissue-specific responses in mutator mice.
  36. The Genetic Landscape of a Metabolic Interaction.
  1. Cell Metab. 2023 Aug 22. pii: S1550-4131(23)00289-9. [Epub ahead of print]
    Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
    Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson.
      The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.
    Keywords:  OXPHOS; mitochondria; mitochondrial respirasomes; supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.015
  2. Onco Targets Ther. 2023 ;16 695-702
    Spotlight on GOT2 in Cancer Metabolism.
    Samuel A Kerk, Javier Garcia-Bermudez, Kivanc Birsoy, Mara H Sherman, Yatrik M Shah, Costas A Lyssiotis.
      GOT2 is at the nexus of several critical metabolic pathways in homeostatic cellular and dysregulated cancer metabolism. Despite this, recent work has emphasized the remarkable plasticity of cancer cells to employ compensatory pathways when GOT2 is inhibited. Here, we review the metabolic roles of GOT2, highlighting findings in both normal and cancer cells. We emphasize how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT2 is inhibited. We close by using this framework to discuss key considerations for future investigations into cancer metabolism.
    Keywords:  mitochondria; nucleotides; pancreatic cancer; redox; transaminase; tumor microenvironment
    DOI:  https://doi.org/10.2147/OTT.S382161
  3. Cell Rep. 2023 Aug 29. pii: S2211-1247(23)01054-9. [Epub ahead of print]42(9): 113043
    The malate-aspartate shuttle is important for de novo serine biosynthesis.
    Melissa H Broeks, Nils W F Meijer, Denise Westland, Marjolein Bosma, Johan Gerrits, Hannah M German, Jolita Ciapaite, Clara D M van Karnebeek, Ronald J A Wanders, Fried J T Zwartkruis, Nanda M Verhoeven-Duif, Judith J M Jans.
      The malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.
    Keywords:  CP: Metabolism; NADH shuttle; central carbon metabolism; glycolysis; isotope-tracer analysis; malate dehydrogenase; malate-aspartate shuttle; metabolomics; serine biosynthesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113043
  4. PLoS Genet. 2023 Aug 28. 19(8): e1010904
    MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.
    Juliana Cazarin, Rachel E DeRollo, Siti Noor Ain Binti Ahmad Shahidan, Jamison B Burchett, Daniel Mwangi, Saikumari Krishnaiah, Annie L Hsieh, Zandra E Walton, Rebekah Brooks, Stephano S Mello, Aalim M Weljie, Chi V Dang, Brian J Altman.
      The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
    DOI:  https://doi.org/10.1371/journal.pgen.1010904
  5. Nat Metab. 2023 Aug 28.
    A yeast vacuolar pH 'heartbeat' coordinates amino acid metabolism and the cell cycle.
    Patricia M Kane.
      
    DOI:  https://doi.org/10.1038/s42255-023-00875-y
  6. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01024-0. [Epub ahead of print]42(9): 113013
    The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.
    Iosifina P Foskolou, Pedro P Cunha, Elena Sánchez-López, Eleanor A Minogue, Benoît P Nicolet, Aurélie Guislain, Christian Jorgensen, Sarantos Kostidis, Nordin D Zandhuis, Laura Barbieri, David Bargiela, Demitris Nathanael, Petros A Tyrakis, Asis Palazon, Martin Giera, Monika C Wolkers, Randall S Johnson.
      2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.
    Keywords:  2-hydroxyglutarate; CD8+ T cell function; CD8+ T cell memory; CP: Immunology; adoptive cell transfer; oncometabolites
    DOI:  https://doi.org/10.1016/j.celrep.2023.113013
  7. Nat Metab. 2023 Aug 31.
    Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
    Abir Mukherjee, Divya Bezwada, Francesco Greco, Malu Zandbergen, Tong Shen, Chun-Yi Chiang, Medine Tasdemir, Johannes Fahrmann, Dmitry Grapov, Michael R La Frano, Hieu S Vu, Brandon Faubert, John W Newman, Liam A McDonnell, Luigi Nezi, Oliver Fiehn, Ralph J DeBerardinis, Ernst Lengyel.
      In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.
    DOI:  https://doi.org/10.1038/s42255-023-00879-8
  8. bioRxiv. 2023 Aug 16. pii: 2023.08.15.553413. [Epub ahead of print]
    The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
    Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.
      Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.
    DOI:  https://doi.org/10.1101/2023.08.15.553413
  9. Nat Metab. 2023 Aug 31.
    A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
    Undiagnosed Diseases Network
      In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00873-0
  10. Mol Cell. 2023 Aug 24. pii: S1097-2765(23)00640-8. [Epub ahead of print]
    Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
    Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian.
      The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.
    Keywords:  AhR; cancer therapy; cysteine; cystine; ferroptosis; lysosome; mRNA; nutrient stress
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.004
  11. Biomed Pharmacother. 2023 Aug 24. pii: S0753-3322(23)01133-2. [Epub ahead of print]166 115342
    Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
    Yongjian Guo, Chengju Luo, Yuening Sun, Wenjing Guo, Ruitian Zhang, Xin Zhang, Xue Ke, Libin Wei.
      Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.
    Keywords:  Glucose restriction; Mitochondrial fusion; Mitochondrial metabolic plasticity; Oroxylin A
    DOI:  https://doi.org/10.1016/j.biopha.2023.115342
  12. Basic Res Cardiol. 2023 Aug 28. 118(1): 34
    Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.
    Hiran A Prag, Michael P Murphy, Thomas Krieg.
      In the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for damage during ischaemia/reperfusion (I/R) injury. Here we outline the necessary conditions for superoxide production by RET at complex I and how it can occur during reperfusion. In addition, we explore various pathways that are implicated in generating the conditions for RET to occur and suggest potential therapeutic strategies to target RET, aiming to achieve cardioprotection.
    Keywords:  Malonate; Mitochondria; Reactive oxygen species; Reverse electron transport; Succinate; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s00395-023-01002-4
  13. Trends Cancer. 2023 Aug 30. pii: S2405-8033(23)00168-1. [Epub ahead of print]
    Interferon signaling restrains renal cell carcinoma heterogeneity.
    Peter Holicek, Jitka Fucikova, Lorenzo Galluzzi.
      Type I interferon (IFN) is central to cancer surveillance as it mediates both direct and immune-mediated oncosuppressive effects. A recent study by Perelli et al. suggests that the ability of renal cancer cells to tolerate complex karyotypic alterations elicited by chromosomal instability (CIN), and ultimately acquire full metastatic potential, is also negatively regulated by IFN signaling.
    Keywords:  CGAS; CNV; cancer stem cells; cancer/immunity coevolution; immunoevasion
    DOI:  https://doi.org/10.1016/j.trecan.2023.08.008
  14. Nature. 2023 Aug 30.
    Metabolic programs of T cell tissue residency empower tumour immunity.
    Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian T Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J Justin Milner, Kenneth H Hu, Amy Vichaidit, Natalie Santillano, Brigid S Boland, John T Chang, Mohit Jain, Sonia Sharma, Matthew F Krummel, Hongbo Chi, Steven J Bensinger, Ananda W Goldrath.
      Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.
    DOI:  https://doi.org/10.1038/s41586-023-06483-w
  15. Dev Cell. 2023 Aug 22. pii: S1534-5807(23)00403-3. [Epub ahead of print]
    Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells.
    Zong-Heng Wang, Wenjing Zhao, Christian A Combs, Fan Zhang, Jay R Knutson, Mary A Lilly, Hong Xu.
      In multicellular lives, the differentiation of stem cells and progenitor cells is often accompanied by a transition from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). However, the underlying mechanism of this metabolic transition remains largely unknown. In this study, we investigate the role of mechanical stress in activating OXPHOS during differentiation of the female germline cyst in Drosophila. We demonstrate that the surrounding somatic cells flatten the 16-cell differentiating cyst, resulting in an increase of the membrane tension of germ cells inside the cyst. This mechanical stress is necessary to maintain cytosolic Ca2+ concentration in germ cells through a mechanically activated channel, transmembrane channel-like. The sustained cytosolic Ca2+ triggers a CaMKI-Fray-JNK signaling relay, leading to the transcriptional activation of OXPHOS in differentiating cysts. Our findings demonstrate a molecular link between cell mechanics and mitochondrial energy metabolism, with implications for other developmentally orchestrated metabolic transitions in mammals.
    Keywords:  CaMKI; Fray; JNK; Myc; TMC; calcium; mechanotransduction; mitochondria; oogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.007
  16. Biochem Soc Trans. 2023 Aug 29. pii: BST20230012. [Epub ahead of print]
    Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
    Sandra H Lee, Hannah E Duron, Dipayan Chaudhuri.
      While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.
    Keywords:  MCU; NCLX; electron transport chain; mitochondrial dysfunction; mitochondrial permeability transition pores; oxidative phosphorylation
    DOI:  https://doi.org/10.1042/BST20230012
  17. Trends Endocrinol Metab. 2023 Aug 28. pii: S1043-2760(23)00161-3. [Epub ahead of print]
    Unleashing ferroptosis for cancer therapy with warfarin.
    Xiaoguang Liu, Li Zhuang, Boyi Gan.
      Ferroptosis holds promise for cancer therapy. A recent study by Yang et al. in Cell Metabolism reveals that VKORC1L1-mediated reduction of vitamin K inhibits ferroptosis and establishes a direct p53-VKORC1L1 link in its regulation. As warfarin can inhibit VKORC1L1, the study further underscores this drug's potential as a cancer therapy.
    Keywords:  VKORC1L1; ferroptosis; p53; vitamin K; warfarin
    DOI:  https://doi.org/10.1016/j.tem.2023.08.008
  18. Life Sci Alliance. 2023 Nov;pii: e202302271. [Epub ahead of print]6(11):
    T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
    Imogen G Franklin, Paul Milne, Jordan Childs, Róisín M Boggan, Isabel Barrow, Conor Lawless, Gráinne S Gorman, Yi Shiau Ng, Matthew Collin, Oliver M Russell, Sarah J Pickett.
      Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.
    DOI:  https://doi.org/10.26508/lsa.202302271
  19. Trends Endocrinol Metab. 2023 Aug 24. pii: S1043-2760(23)00152-2. [Epub ahead of print]
    Lysosomal glucose sensing and glycophagy in metabolism.
    Melina C Mancini, Robert C Noland, J Jason Collier, Susan J Burke, Krisztian Stadler, Timothy D Heden.
      Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism is unrefined. This review will highlight the role of the lysosome in glucose metabolism with a focus on lysosomal glucose and glycogen sensing, glycophagy, and lysosomal glucose transport and how these processes impact autophagy and energy metabolism. Additionally, the role of lysosomal glucose metabolism in genetic and metabolic diseases will be briefly discussed.
    Keywords:  autophagy; carbohydrate sensing; glycogen; nutrient sensing
    DOI:  https://doi.org/10.1016/j.tem.2023.07.008
  20. Nat Metab. 2023 Aug 28.
    Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
    Voytek Okreglak, Rachel Ling, Maria Ingaramo, Nathaniel H Thayer, Alfred Millett-Sikking, Daniel E Gottschling.
      Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide. The vacuolar pH dynamics require the uptake of extracellular amino acids and activity of TORC1, the v-ATPase and the cycling of the vacuolar specific lipid phosphatidylinositol 3,5-bisphosphate, which is regulated by the cyclin-dependent kinase Pho85 (CDK5 in mammals). Vacuolar pH regulation enables amino acid sequestration and mobilization from the organelle, which is important for mitochondrial function, ribosome homeostasis and cell size control. Collectively, our data provide a new paradigm for the use of dynamic pH-dependent amino acid compartmentalization during cell growth/division.
    DOI:  https://doi.org/10.1038/s42255-023-00872-1
  21. Methods Mol Biol. 2024 ;2713 363-376
    Measuring the Metabolic State of Tissue-Resident Macrophages via SCENITH.
    Andrea Vogel, Paulina García González, Rafael J Argüello.
      Functional reprograming of cells is linked to a process of metabolic rewiring that is adapted for such new functions or microenvironment. Macrophages are present in all tissues and exposed to different microenvironments throughout our body. Profiling energetic metabolism of tissue resident and other heterogeneous populations of macrophages in vitro and ex vivo is technologically very challenging. We have recently developed a method to functionally profile energetic metabolism with single-cell resolution, named SCENITH. This method can be performed rapidly ex vivo and does not require specialized equipment. In this book chapter, we will summarize the tissue processing, the procedure and methods, the analysis and example of results, and a series of frequently asked questions.
    Keywords:  Energetic metabolism; FACS; Flow cytometry; Glycolytic capacity; Immunometabolism; Macrophages; Metabolic dependencies; Mitochondrial dependence; Protein synthesis; SCENITH; Single-cell resolution
    DOI:  https://doi.org/10.1007/978-1-0716-3437-0_25
  22. Genes Dev. 2023 Aug 30.
    Metabolic partitioning in the brain and its hijacking by glioblastoma.
    Jed de Ruiter Swain, Evdokia Michalopoulou, Evan K Noch, Michael J Lukey, Linda Van Aelst.
      The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.
    Keywords:  IDH mutation; brain metabolism; cancer metabolism; glioblastoma; glioma; glioma therapy; immune suppression; tumor microenvironment
    DOI:  https://doi.org/10.1101/gad.350693.123
  23. Nature. 2023 Aug 30.
    Identification of an alternative triglyceride biosynthesis pathway.
    Gian-Luca McLelland, Marta Lopez-Osias, Cristy R C Verzijl, Brecht D Ellenbroek, Rafaela A Oliveira, Nicolaas J Boon, Marleen Dekker, Lisa G van den Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim van Zutphen, Johan W Jonker, Thijn R Brummelkamp.
      Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
    DOI:  https://doi.org/10.1038/s41586-023-06497-4
  24. J Cell Sci. 2023 Sep 01. pii: jcs260857. [Epub ahead of print]136(17):
    Mitochondrial phospholipid metabolism in health and disease.
    Alaumy Joshi, Travis H Richard, Vishal M Gohil.
      Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology. Studies on inter-organellar and intramitochondrial phospholipid transport have significantly advanced our understanding of the mechanisms that maintain mitochondrial phospholipid homeostasis. Here, we discuss these recent advances in the function and transport of mitochondrial phospholipids while describing their biochemical and biophysical properties and biosynthetic pathways. Additionally, we highlight the roles of mitochondrial phospholipids in human health by describing the various genetic diseases caused by disruptions in their biosynthesis and discuss advances in therapeutic strategies for Barth syndrome, the best-studied disorder of mitochondrial phospholipid metabolism.
    Keywords:  Barth syndrome; Cardiolipin; Membranes; Mitochondria; Phosphatidylethanolamine; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.260857
  25. Nat Aging. 2023 Aug 31.
    Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
    Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini.
      Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
    DOI:  https://doi.org/10.1038/s43587-023-00473-3
  26. bioRxiv. 2023 Aug 14. pii: 2023.08.11.552957. [Epub ahead of print]
    Machine learning of cellular metabolic rewiring.
    Joao B Xavier.
      Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here we introduce MetaboLiteLearner , a machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry (GC/MS) to predict abundance changes in metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner successfully predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. Our analysis highlights shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting potential organ-tailored cellular adaptations. MetaboLiteLearner 's integration of machine learning and metabolomics paves the way for new insights into complex cellular adaptations.Significance: Metabolic rewiring-the cellular adaptation to shifts in environment and nutrients-plays key roles in many contexts, including cancer metastasis. Traditional metabolomics often falls short of capturing the nuances of these metabolic shifts. This work introduces MetaboliLiteLearner , a machine learning framework that harnesses the rich fragmentation patterns from electron ionization collected in scan mode during gas chromatography/mass spectrometry, paving the way for enhanced insights into metabolic adaptations. Demonstrating its robustness on a breast cancer model, we highlight MetaboliLiteLearner 's potential to reshape our understanding of metabolic rewiring, with implications in diagnostics, therapeutics, and basic cell biology.
    DOI:  https://doi.org/10.1101/2023.08.11.552957
  27. Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01045-8. [Epub ahead of print]42(9): 113034
    Formate promotes invasion and metastasis in reliance on lipid metabolism.
    Catherine Delbrouck, Nicole Kiweler, Oleg Chen, Vitaly I Pozdeev, Lara Haase, Laura Neises, Anaïs Oudin, Aymeric Fouquier d'Hérouël, Ruolin Shen, Lisa Schlicker, Rashi Halder, Antoine Lesur, Anne Schuster, Nadja I Lorenz, Christian Jaeger, Maureen Feucherolles, Gilles Frache, Martyna Szpakowska, Andy Chevigne, Michael W Ronellenfitsch, Etienne Moussay, Marie Piraud, Alexander Skupin, Almut Schulze, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.
      Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.
    Keywords:  CP: Cancer; CP: Metabolism; cancer metastasis; formate overflow; invasion; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113034
  28. Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01058-6. [Epub ahead of print]42(9): 113047
    Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.
    Mengdi Guo, Diala Abd-Rabbo, Bruna C Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks.
      CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.
    Keywords:  CD4 T cell; CP: Immunology; CTLA4; T regulatory cell; cancer; dysfunction; exhaustion; immunotherapy; metabolism; transcriptomic signature; tumor immunology
    DOI:  https://doi.org/10.1016/j.celrep.2023.113047
  29. bioRxiv. 2023 Aug 19. pii: 2023.08.17.553736. [Epub ahead of print]
    Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
    Paul V Dellorusso, Melissa A Proven, Fernando J Calero-Nieto, Xiaonan Wang, Carl A Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W Swann, Theodore T Ho, Zhiyu Zhao, Sean C Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué.
      Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction ( 1 ). Autophagy is central for the benefits associated with activation of longevity signaling programs ( 2 ), and for HSC function and response to nutrient stress ( 3,4 ). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional ( 4 ). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche ( 5 ). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.One-Sentence Summary: Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.
    DOI:  https://doi.org/10.1101/2023.08.17.553736
  30. J Proteomics. 2023 Aug 30. pii: S1874-3919(23)00187-2. [Epub ahead of print] 104998
    Proteomic analysis of murine kidney proximal tubule sub-segment derived cell lines reveals preferences in mitochondrial pathway activity.
    Ricardo Melo Ferreira, Rita de Almeida, Clayton Culp, Frank Witzmann, Mu Wang, Rajesh Kher, Glenn T Nagami, Rodrigo Mohallem, Chaylen Jade Andolino, Uma K Aryal, Michael T Eadon, Robert L Bacallao.
      The proximal tubule (PT) is a nephron segment that is responsible for the majority of solute and water reabsorption in the kidney. Each of its sub-segments have specialized functions; however, little is known about the genes and proteins that determine the oxidative phosphorylation capacity of the PT sub-segments. This information is critical to understanding kidney function and will provide a comprehensive landscape of renal cell adaptations to injury, physiologic stressors, and development. This study analyzed three immortalized murine renal cell lines (PT S1, S2, and S3 segments) for protein content and compared them to a murine fibroblast cell line. All three proximal tubule cell lines generate ATP predominantly by oxidative phosphorylation while the fibroblast cell line is glycolytic. The proteomic data demonstrates that the most significant difference in proteomic signatures between the cell lines are proteins known to be localized in the nucleus followed by mitochondrial proteins. Mitochondrial metabolic substrate utilization assays were performed using the proximal tubule cell lines to determine substrate utilization kinetics thereby providing a physiologic context to the proteomic dataset. This data will allow researchers to study differences in nephron-specific cell lines, between epithelial and fibroblast cells, and between actively respiring cells and glycolytic cells. SIGNIFICANCE: Proteomic analysis of proteins expressed in immortalized murine renal proximal tubule cells was compared to a murine fibroblast cell line proteome. The proximal tubule segment specific cell lines: S1, S2 and S3 are all grown under conditions whereby the cells generate ATP by oxidative phosphorylation while the fibroblast cell line utilizes anaerobic glycolysis for ATP generation. The proteomic studies allow for the following queries: 1) comparisons between the proximal tubule segment specific cell lines, 2) comparisons between polarized epithelia and fibroblasts, 3) comparison between cells employing oxidative phosphorylation versus anaerobic glycolysis and 4) comparisons between cells grown on clear versus opaque membrane supports. The data finds major differences in nuclear protein expression and mitochondrial proteins. This proteomic data set will be an important baseline dataset for investigators who need immortalized renal proximal tubule epithelial cells for their research.
    Keywords:  Fibroblast; Metabolism; Mitochondria; Nucleus; Proteomic analysis; Proximal tubule; Renal epithelial cells
    DOI:  https://doi.org/10.1016/j.jprot.2023.104998
  31. Nature. 2023 Aug 30.
    CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.
    Murad R Mamedov, Shane Vedova, Jacob W Freimer, Avinash Das Sahu, Amrita Ramesh, Maya M Arce, Angelo D Meringa, Mineto Ota, Peixin Amy Chen, Kristina Hanspers, Vinh Q Nguyen, Kirsten A Takeshima, Anne C Rios, Jonathan K Pritchard, Jürgen Kuball, Zsolt Sebestyen, Erin J Adams, Alexander Marson.
      γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1-5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells4-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6-8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.
    DOI:  https://doi.org/10.1038/s41586-023-06482-x
  32. Nat Biomed Eng. 2023 Aug 28.
    Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission.
    Sue Zhang, Gabrielle Grifno, Rachel Passaro, Kathryn Regan, Siyi Zheng, Muhamed Hadzipasic, Rohin Banerji, Logan O'Connor, Vinson Chu, Sung Yeon Kim, Jiarui Yang, Linzheng Shi, Kavon Karrobi, Darren Roblyer, Mark W Grinstaff, Hadi T Nia.
      In cancer, solid stresses impede the delivery of therapeutics to tumours and the trafficking and tumour infiltration of immune cells. Understanding such consequences and the origin of solid stresses requires their probing in vivo at the cellular scale. Here we report a method for performing volumetric and longitudinal measurements of solid stresses in vivo, and findings from its applicability to tumours. We used multimodal intravital microscopy of fluorescently labelled polyacrylamide beads injected in breast tumours in mice as well as mathematical modelling to compare solid stresses at the single-cell and tissue scales, in primary and metastatic tumours, in vitro and in mice, and in live mice and post-mortem tissue. We found that solid-stress transmission is scale dependent, with tumour cells experiencing lower stresses than their embedding tissue, and that tumour cells in lung metastases experience substantially higher solid stresses than those in the primary tumours. The dependence of solid stresses on length scale and the microenvironment may inform the development of therapeutics that sensitize cancer cells to such mechanical forces.
    DOI:  https://doi.org/10.1038/s41551-023-01080-8
  33. Nat Metab. 2023 Aug 31.
    Astrocytic GABA in LHA is an obesity 'thermostat'.
    Ismael González-García, Cristina García-Cáceres.
      
    DOI:  https://doi.org/10.1038/s42255-023-00849-0
  34. Nature. 2023 Sep;621(7977): 47-48
    Previously unknown pathway for lipid biosynthesis discovered.
    Jean E Schaffer.
      
    Keywords:  Biochemistry; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-02502-y
  35. Life Sci Alliance. 2023 Nov;pii: e202302036. [Epub ahead of print]6(11):
    Alternative oxidase causes cell type- and tissue-specific responses in mutator mice.
    Lilli Ikonen, Sini Pirnes-Karhu, Swagat Pradhan, Howard T Jacobs, Marten Szibor, Anu Suomalainen.
      Energetic insufficiency, excess production of reactive oxygen species (ROS), and aberrant signaling partially account for the diverse pathology of mitochondrial diseases. Whether interventions affecting ROS, a regulator of stem cell pools, could modify somatic stem cell homeostasis remains unknown. Previous data from mitochondrial DNA mutator mice showed that increased ROS leads to oxidative damage in erythroid progenitors, causing lifespan-limiting anemia. Also unclear is how ROS-targeted interventions affect terminally differentiated tissues. Here, we set out to test in mitochondrial DNA mutator mice how ubiquitous expression of the Ciona intestinalis alternative oxidase (AOX), which attenuates ROS production, affects murine stem cell pools. We found that AOX does not affect neural stem cells but delays the progression of mutator-driven anemia. Furthermore, when combined with the mutator, AOX potentiates mitochondrial stress and inflammatory responses in skeletal muscle. These differential cell type-specific findings demonstrate that AOX expression is not a global panacea for curing mitochondrial dysfunction. ROS attenuation must be carefully studied regarding specific underlying defects before AOX can be safely used in therapy.
    DOI:  https://doi.org/10.26508/lsa.202302036
  36. bioRxiv. 2023 Aug 17. pii: 2023.05.28.542639. [Epub ahead of print]
    The Genetic Landscape of a Metabolic Interaction.
    Thuy N Nguyen, Christine Ingle, Samuel Thompson, Kimberly A Reynolds.
      Enzyme abundance, catalytic activity, and ultimately sequence are all shaped by the need of growing cells to maintain metabolic flux while minimizing accumulation of deleterious intermediates. While much prior work has explored the constraints on protein sequence and evolution induced by physical protein-protein interactions, the sequence-level constraints emerging from non-binding functional interactions in metabolism remain unclear. To quantify how variation in the activity of one enzyme constrains the biochemical parameters and sequence of another, we focused on dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS), a pair of enzymes catalyzing consecutive reactions in folate metabolism. We used deep mutational scanning to quantify the growth rate effect of 2,696 DHFR single mutations in 3 TYMS backgrounds under conditions selected to emphasize biochemical epistasis. Our data are well-described by a relatively simple enzyme velocity to growth rate model that quantifies how metabolic context tunes enzyme mutational tolerance. Together our results reveal the structural distribution of epistasis in a metabolic enzyme and establish a foundation for the design of multi-enzyme systems.
    DOI:  https://doi.org/10.1101/2023.05.28.542639
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