bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–01–14
fifty-four papers selected by
Christian Frezza, Universität zu Köln
  1. Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
  2. Immunosurveillance encounters cancer metabolism.
  3. Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
  4. Effects of aging on glucose and lipid metabolism in mice.
  5. Local and dynamic regulation of neuronal glycolysis in vivo.
  6. Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.
  7. Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
  8. METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.
  9. The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression.
  10. Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners.
  11. Recreating metabolic interactions of the tumour microenvironment.
  12. TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.
  13. Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma.
  14. Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.
  15. Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
  16. Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.
  17. Hitting the Sweet Spot: How Glucose Metabolism Is Orchestrated in Space and Time by Phosphofructokinase-1.
  18. Evaluating the Adaptive Fitness of Circadian Clocks and their Evolution.
  19. Post-translational modulation of cell signalling through protein succinylation.
  20. The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
  21. LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells.
  22. Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
  23. Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.
  24. UCP2 and pancreatic cancer: conscious uncoupling for therapeutic effect.
  25. Serine synthesis promotes bone degradation.
  26. Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate.
  27. Exercise induces tissue-specific adaptations to enhance cardiometabolic health.
  28. Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
  29. Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation.
  30. Succinate dehydrogenase deficient renal cell carcinoma: A case report of an uncommon renal cancer.
  31. Unexpected roles for AMPK in suppression of autophagy and reactivation of mTORC1 signaling during prolonged amino acid deprivation.
  32. Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer.
  33. Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol.
  34. Ironing out the mitochondria.
  35. Tumor iron homeostasis and immune regulation.
  36. Sex affects cancer genomes.
  37. Kidney macrophages tap the stream.
  38. Cell origin of BRCA2-mutant breast cancer.
  39. Age-regulated cycling metabolites are relevant for behavior.
  40. Consequences of the cost of living: is variation in metabolic rate evolutionarily significant?
  41. The Untargeted Metabolomics Reveals Differences in Energy Metabolism in Patients with Different Subtypes of Ischemic Stroke.
  42. Cholesterol biosynthetic pathway induces cellular senescence through ERRα.
  43. Ketone Bodies in Cell Physiology and Cancer.
  44. The chromatin landscape of healthy and injured cell types in the human kidney.
  45. Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.
  46. Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice.
  47. A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.
  48. Cristae shaping and dynamics in mitochondrial function.
  49. Electro-metabolic signaling.
  50. Tissue-specific metabolic enzyme levels covary with whole-animal metabolic rates and life-history loci via epistatic effects.
  51. Estimating the relationship between fitness and metabolic rate: which rate should we use?
  52. Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape.
  53. A novel computational tool for tracking cancer energy hijacking from immune cells.
  54. Unsupervised and supervised discovery of tissue cellular neighborhoods from cell phenotypes.
  1. J Biol Chem. 2024 Jan 08. pii: S0021-9258(24)00002-4. [Epub ahead of print] 105626
    Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
    Gaganvir Parmar, Claire Fong-McMaster, Chantal Pileggi, David A Patten, Alexanne Cuillerier, Stephanie Myers, Ying Wang, Siegfried Hekimi, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Mitochondrial electron transport chain (ETC) complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SC remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in TCA cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.
    Keywords:  Mitochondria; NDUFB4; electron transport chain; oxidative phosphorylation; respirasome; steady-state metabolomics; supercomplexes
    DOI:  https://doi.org/10.1016/j.jbc.2024.105626
  2. EMBO Rep. 2024 Jan 12.
    Immunosurveillance encounters cancer metabolism.
    Yu-Ming Chuang, Sheue-Fen Tzeng, Ping-Chih Ho, Chin-Hsien Tsai.
      Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.
    Keywords:  Cancer Evolution; Immunoediting; Immunometabolism
    DOI:  https://doi.org/10.1038/s44319-023-00038-w
  3. Cell. 2024 Jan 05. pii: S0092-8674(23)01342-9. [Epub ahead of print]
    Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
    Joshua D Meisel, Maria Miranda, Owen S Skinner, Presli P Wiesenthal, Sandra M Wellner, Alexis A Jourdain, Gary Ruvkun, Vamsi K Mootha.
      The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.
    Keywords:  C. elegans; NADH:ubiquinone oxidoreductase; NDUFA6; NDUFS4; complex I; electron transport chain; hyperoxia; hypoxia; mitochondria; oxygen
    DOI:  https://doi.org/10.1016/j.cell.2023.12.010
  4. bioRxiv. 2023 Dec 18. pii: 2023.12.17.572088. [Epub ahead of print]
    Effects of aging on glucose and lipid metabolism in mice.
    Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.
      Aging is accompanied by multiple molecular changes that contribute to aging-associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part because mitochondria are central to cellular metabolism. Moreover, the co-factor NAD+, which is reported to decline across multiple tissue types during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and Diversity Outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of up-regulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. Because mitochondrial respiration, a major source of NAD+ regeneration, is reported to decline with age, our data supports a model where NAD+-generating lipid metabolism reactions may buffer against changes in NAD+/NADH during healthy aging.
    DOI:  https://doi.org/10.1101/2023.12.17.572088
  5. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2314699121
    Local and dynamic regulation of neuronal glycolysis in vivo.
    Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Ian J Gonzalez, Marc Hammarlund, Anthony A Hyman, Philip J S Stork, Richard H Goodman, Daniel A Colón-Ramos.
      Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, for use in Caenorhabditis elegans to image dynamic changes in glycolysis within individual neurons and in vivo. We determined that neurons cell-autonomously perform glycolysis and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function and uncovers unique relationships between neuronal identities and metabolic landscapes in vivo.
    Keywords:  C. elegans; biosensor; energy metabolism; glycolysis; neurons
    DOI:  https://doi.org/10.1073/pnas.2314699121
  6. bioRxiv. 2023 Dec 24. pii: 2023.12.24.573250. [Epub ahead of print]
    Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.
    Keene L Abbott, Ahmed Ali, Bradley I Reinfeld, Amy Deik, Sonu Subudhi, Madelyn D Landis, Rachel A Hongo, Kirsten L Young, Tenzin Kunchok, Christopher S Nabel, Kayla D Crowder, Johnathan R Kent, Maria Lucia L Madariaga, Rakesh K Jain, Kathryn E Beckermann, Caroline A Lewis, Clary B Clish, Alexander Muir, W Kimryn Rathmell, Jeffrey C Rathmell, Matthew G Vander Heiden.
      The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.
    DOI:  https://doi.org/10.1101/2023.12.24.573250
  7. EMBO J. 2024 Jan 11.
    Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
    Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.
      Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
    Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-023-00008-x
  8. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01035-3. [Epub ahead of print]
    METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.
    Tslil Ast, Yuzuru Itoh, Shayan Sadre, Jason G McCoy, Gil Namkoong, Jordan C Wengrod, Ivan Chicherin, Pallavi R Joshi, Piotr Kamenski, Daniel L M Suess, Alexey Amunts, Vamsi K Mootha.
      Friedreich's ataxia (FA) is a debilitating, multisystemic disease caused by the depletion of frataxin (FXN), a mitochondrial iron-sulfur (Fe-S) cluster biogenesis factor. To understand the cellular pathogenesis of FA, we performed quantitative proteomics in FXN-deficient human cells. Nearly every annotated Fe-S cluster-containing protein was depleted, indicating that as a rule, cluster binding confers stability to Fe-S proteins. We also observed depletion of a small mitoribosomal assembly factor METTL17 and evidence of impaired mitochondrial translation. Using comparative sequence analysis, mutagenesis, biochemistry, and cryoelectron microscopy, we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability. METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.
    Keywords:  FA; Fe-S cluster; Friedreich’s ataxia; METTL17; frataxin; mitochondria; mitoribosome
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.016
  9. Nat Metab. 2024 Jan 10.
    The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression.
    Steve Stegen, Karen Moermans, Ingrid Stockmans, Bernard Thienpont, Geert Carmeliet.
      Bone-resorbing osteoclasts are vital for postnatal bone health, as increased differentiation or activity results in skeletal pathologies such as osteoporosis. The metabolism of mature osteoclasts differs from their progenitor cells, but whether the observed metabolic changes are secondary to the altered cell state or actively drive the process of cell differentiation is unknown. Here, we show that transient activation of the serine synthesis pathway (SSP) is essential for osteoclastogenesis, as deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase in osteoclast progenitors impairs their differentiation and results in increased bone mass. In addition, pharmacological phosphoglycerate dehydrogenase inhibition abrogated bone loss in a mouse model of postmenopausal osteoporosis by blocking bone resorption. Mechanistically, SSP-derived α-ketoglutarate is necessary for histone demethylases that remove repressive histone methylation marks at the nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) gene locus, thereby inducing NFATc1 expression and consequent osteoclast maturation. Taken together, this study reveals a metabolic-epigenetic coupling mechanism that directs osteoclast differentiation and suggests that the SSP can be therapeutically targeted to prevent osteoporotic bone loss.
    DOI:  https://doi.org/10.1038/s42255-023-00948-y
  10. Nat Commun. 2024 Jan 11. 15(1): 473
    Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners.
    Pankaj Sharma, Elena Maklashina, Markus Voehler, Sona Balintova, Sarka Dvorakova, Michal Kraus, Katerina Hadrava Vanova, Zuzana Nahacka, Renata Zobalova, Stepana Boukalova, Kristyna Cunatova, Tomas Mracek, Hans K Ghayee, Karel Pacak, Jakub Rohlena, Jiri Neuzil, Gary Cecchini, T M Iverson.
      Complex II (CII) activity controls phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, cancer metabolism, immune activation, and ischemia-reperfusion injury. CII activity can be regulated at the level of assembly, a process that leverages metastable assembly intermediates. The nature of these intermediates and how CII subunits transfer between metastable complexes remains unclear. In this work, we identify metastable species containing the SDHA subunit and its assembly factors, and we assign a preferred temporal sequence of appearance of these species during CII assembly. Structures of two species show that the assembly factors undergo disordered-to-ordered transitions without the appearance of significant secondary structure. The findings identify that intrinsically disordered regions are critical in regulating CII assembly, an observation that has implications for the control of assembly in other biomolecular complexes.
    DOI:  https://doi.org/10.1038/s41467-023-44563-7
  11. Trends Endocrinol Metab. 2024 Jan 10. pii: S1043-2760(23)00250-3. [Epub ahead of print]
    Recreating metabolic interactions of the tumour microenvironment.
    Rodrigo Curvello, Nikolaus Berndt, Sandra Hauser, Daniela Loessner.
      Tumours are heterogeneous tissues containing diverse populations of cells and an abundant extracellular matrix (ECM). This tumour microenvironment prompts cancer cells to adapt their metabolism to survive and grow. Besides epigenetic factors, the metabolism of cancer cells is shaped by crosstalk with stromal cells and extracellular components. To date, most experimental models neglect the complexity of the tumour microenvironment and its relevance in regulating the dynamics of the metabolism in cancer. We discuss emerging strategies to model cellular and extracellular aspects of cancer metabolism. We highlight cancer models based on bioengineering, animal, and mathematical approaches to recreate cell-cell and cell-matrix interactions and patient-specific metabolism. Combining these approaches will improve our understanding of cancer metabolism and support the development of metabolism-targeting therapies.
    Keywords:  cancer metabolism; cancer models; mathematical models; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.tem.2023.12.005
  12. Nat Commun. 2024 Jan 09. 15(1): 406
    TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex.
    Nicola Alesi, Damir Khabibullin, Dean M Rosenthal, Elie W Akl, Pieter M Cory, Michel Alchoueiry, Samer Salem, Melissa Daou, William F Gibbons, Jennifer A Chen, Long Zhang, Harilaos Filippakis, Laura Graciotti, Caterina Miceli, Jlenia Monfregola, Claudia Vilardo, Manrico Morroni, Chiara Di Malta, Gennaro Napolitano, Andrea Ballabio, Elizabeth P Henske.
      Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions  in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41467-023-44229-4
  13. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01029-8. [Epub ahead of print]
    Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma.
    Lianxin Hu, Yanfeng Zhang, Lei Guo, Hua Zhong, Ling Xie, Jin Zhou, Chengheng Liao, Hongwei Yao, Jun Fang, Hongyi Liu, Cheng Zhang, Hui Zhang, Xiaoqiang Zhu, Maowu Luo, Alex von Kriegsheim, Bufan Li, Weibo Luo, Xuewu Zhang, Xian Chen, Joshua T Mendell, Lin Xu, Payal Kapur, Albert S Baldwin, James Brugarolas, Qing Zhang.
      TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.
    Keywords:  DCLK2; NMD pathway; TBK1; ccRCC; oncogene
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.010
  14. EMBO J. 2024 Jan 11.
    Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.
    Quanjiang Zhang, Zhonggang Li, Qiuxia Li, Samuel Aj Trammell, Mark S Schmidt, Karla Maria Pires, Jinjin Cai, Yuan Zhang, Helena Kenny, Sihem Boudina, Charles Brenner, E Dale Abel.
      Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+.
    Keywords:  Autophagic Flux; Heart Dysfunction; Mitochondrial Homeostasis; NAD+ Metabolism
    DOI:  https://doi.org/10.1038/s44318-023-00009-w
  15. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2307904121
    Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
    Neal K Bennett, Megan Lee, Adam L Orr, Ken Nakamura.
      Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS-based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III, and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP, and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.
    Keywords:  ATP; CRISPRi; ROS; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2307904121
  16. Cold Spring Harb Perspect Med. 2024 Jan 08. pii: a041537. [Epub ahead of print]
    Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.
    Kathryn Gunn, Julie-Aurore Losman.
      Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in IDH1 and IDH2 occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). (R)-2HG accumulation in IDH-mutant tumors results in profound dysregulation of cellular metabolism. The most well-characterized oncogenic effects of (R)-2HG involve the dysregulation of 2OG-dependent epigenetic tumor-suppressor enzymes. However, (R)-2HG has many other effects in IDH-mutant cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated IDH mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target IDH-mutant tumors.
    DOI:  https://doi.org/10.1101/cshperspect.a041537
  17. Cancers (Basel). 2023 Dec 19. pii: 16. [Epub ahead of print]16(1):
    Hitting the Sweet Spot: How Glucose Metabolism Is Orchestrated in Space and Time by Phosphofructokinase-1.
    Melissa Campos, Lauren V Albrecht.
      Glycolysis is the central metabolic pathway across all kingdoms of life. Intensive research efforts have been devoted to understanding the tightly orchestrated processes of converting glucose into energy in health and disease. Our review highlights the advances in knowledge of how metabolic and gene networks are integrated through the precise spatiotemporal compartmentalization of rate-limiting enzymes. We provide an overview of technically innovative approaches that have been applied to study phosphofructokinase-1 (PFK1), which represents the fate-determining step of oxidative glucose metabolism. Specifically, we discuss fast-acting chemical biology and optogenetic tools that have delineated new links between metabolite fluxes and transcriptional reprogramming, which operate together to enact tissue-specific processes. Finally, we discuss how recent paradigm-shifting insights into the fundamental basis of glycolytic regulatory control have shed light on the mechanisms of tumorigenesis and could provide insight into new therapeutic vulnerabilities in cancer.
    Keywords:  cancer; compartmentalization; condensate; glucosome; glycolysis; localization; optogenetics; phosphofructokinase-1; spatiotemporal; subcellular
    DOI:  https://doi.org/10.3390/cancers16010016
  18. J Biol Rhythms. 2024 Jan 07. 7487304231219206
    Evaluating the Adaptive Fitness of Circadian Clocks and their Evolution.
    Maria Luísa Jabbur, Chitrang Dani, Kamiel Spoelstra, Antony N Dodd, Carl Hirschie Johnson.
      Surely most chronobiologists believe circadian clocks are an adaptation of organisms that enhances fitness, but are we certain that this focus of our research effort really confers a fitness advantage? What is the evidence, and how do we evaluate it? What are the best criteria? These questions are the topic of this review. In addition, we will discuss selective pressures that might have led to the historical evolution of circadian systems while considering the intriguing question of whether the ongoing climate change is modulating these selective pressures so that the clock is still evolving.
    Keywords:  chronobiology; circadian; competition assay; cyanobacteria; evolution; fitness; phase angle
    DOI:  https://doi.org/10.1177/07487304231219206
  19. Explor Target Antitumor Ther. 2023 ;4(6): 1260-1285
    Post-translational modulation of cell signalling through protein succinylation.
    Katharina F Kubatzky, Yue Gao, Dayoung Yu.
      Cells need to adapt their activities to extra- and intracellular signalling cues. To translate a received extracellular signal, cells have specific receptors that transmit the signal to downstream proteins so that it can reach the nucleus to initiate or repress gene transcription. Post-translational modifications (PTMs) of proteins are reversible or irreversible chemical modifications that help to further modulate protein activity. The most commonly observed PTMs are the phosphorylation of serine, threonine, and tyrosine residues, followed by acetylation, glycosylation, and amidation. In addition to PTMs that involve the modification of a certain amino acid (phosphorylation, hydrophobic groups for membrane localisation, or chemical groups like acylation), or the conjugation of peptides (SUMOylation, NEDDylation), structural changes such as the formation of disulphide bridge, protein cleavage or splicing can also be classified as PTMs. Recently, it was discovered that metabolites from the tricarboxylic acid (TCA) cycle are not only intermediates that support cellular metabolism but can also modify lysine residues. This has been shown for acetate, succinate, and lactate, among others. Due to the importance of mitochondria for the overall fitness of organisms, the regulatory function of such PTMs is critical for protection from aging, neurodegeneration, or cardiovascular disease. Cancer cells and activated immune cells display a phenotype of accelerated metabolic activity known as the Warburg effect. This metabolic state is characterised by enhanced glycolysis, the use of the pentose phosphate pathway as well as a disruption of the TCA cycle, ultimately causing the accumulation of metabolites like citrate, succinate, and malate. Succinate can then serve as a signalling molecule by directly interacting with proteins, by binding to its G protein-coupled receptor 91 (GPR91) and by post-translationally modifying proteins through succinylation of lysine residues, respectively. This review is focus on the process of protein succinylation and its importance in health and disease.
    Keywords:  Succinate; cancer; immune system; lysine succinylation; metabolites; mitochondria; post-translational modifications
    DOI:  https://doi.org/10.37349/etat.2023.00196
  20. Blood Adv. 2024 Jan 09. 8(1): 56-69
    The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.
    Alan Cunningham, Lieve L Oudejans, Marjan Geugien, Diego Antonio Pereira-Martins, Albertus T J Wierenga, Ayşegül Erdem, Dominique Sternadt, Gerwin Huls, Jan Jacob Schuringa.
       ABSTRACT: Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010786
  21. Nat Cancer. 2024 Jan 09.
    LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells.
    Dhiraj Kumar, Sreeharsha Gurrapu, Yan Wang, Seong-Yeon Bae, Poonam R Pandey, Hong Chen, Jayanta Mondal, Hyunho Han, Chang-Jiun Wu, Spyros Karaiskos, Fei Yang, Aysegul Sahin, Ignacio I Wistuba, Jianjun Gao, Debasish Tripathy, Hua Gao, Benjamin Izar, Filippo G Giancotti.
      The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.
    DOI:  https://doi.org/10.1038/s43018-023-00695-9
  22. Nat Commun. 2024 Jan 11. 15(1): 451
    Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
    Matteo Villa, David E Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E Carrizo, Nisha Rana, Michal A Stanczak, Francesc Baixauli, Katarzyna M Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M Buescher, Edward J Pearce, Erika L Pearce.
      Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
    DOI:  https://doi.org/10.1038/s41467-024-44689-2
  23. Nat Metab. 2024 Jan 09.
    Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.
    Jessica L Huang, Mohammad S Pourhosseinzadeh, Sharon Lee, Niels Krämer, Jaresley V Guillen, Naomi H Cinque, Paola Aniceto, Ariana T Momen, Shinichiro Koike, Mark O Huising.
      While pancreatic β and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that β cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the β cell glucose threshold and consequently lowers the glycaemic set point in vivo.
    DOI:  https://doi.org/10.1038/s42255-023-00944-2
  24. Cancer Metastasis Rev. 2024 Jan 09.
    UCP2 and pancreatic cancer: conscious uncoupling for therapeutic effect.
    Emily G Caggiano, Cullen M Taniguchi.
      Pancreatic cancer has an exaggerated dependence on mitochondrial metabolism, but methods to specifically target the mitochondria without off target effects in normal tissues that rely on these organelles is a significant challenge. The mitochondrial uncoupling protein 2 (UCP2) has potential as a cancer-specific drug target, and thus, we will review the known biology of UCP2 and discuss its potential role in the pathobiology and future therapy of pancreatic cancer.
    Keywords:  Metabolism; Mitochondria; Pancreatic cancer; Therapeutics; Uncoupling
    DOI:  https://doi.org/10.1007/s10555-023-10157-4
  25. Nat Metab. 2024 Jan 10.
    Serine synthesis promotes bone degradation.
    Ryan C Riddle, Gillian M Choquette.
      
    DOI:  https://doi.org/10.1038/s42255-023-00949-x
  26. J Inherit Metab Dis. 2024 Jan 10.
    Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate.
    Sander F Garrelfs, Serhii Chornyi, Heleen Te Brinke, Jos Ruiter, Jaap Groothoff, Ronald J A Wanders.
      Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.
    Keywords:  glyoxylate metabolism; hydroxyproline; hyperoxaluria; mitochondria; oxalate; peroxisomal disorders; peroxisomes
    DOI:  https://doi.org/10.1002/jimd.12711
  27. Cell Metab. 2023 Dec 29. pii: S1550-4131(23)00459-X. [Epub ahead of print]
    Exercise induces tissue-specific adaptations to enhance cardiometabolic health.
    Stephen P Ashcroft, Ben Stocks, Brendan Egan, Juleen R Zierath.
      The risk associated with multiple cancers, cardiovascular disease, diabetes, and all-cause mortality is decreased in individuals who meet the current recommendations for physical activity. Therefore, regular exercise remains a cornerstone in the prevention and treatment of non-communicable diseases. An acute bout of exercise results in the coordinated interaction between multiple tissues to meet the increased energy demand of exercise. Over time, the associated metabolic stress of each individual exercise bout provides the basis for long-term adaptations across tissues, including the cardiovascular system, skeletal muscle, adipose tissue, liver, pancreas, gut, and brain. Therefore, regular exercise is associated with a plethora of benefits throughout the whole body, including improved cardiorespiratory fitness, physical function, and glycemic control. Overall, we summarize the exercise-induced adaptations that occur within multiple tissues and how they converge to ultimately improve cardiometabolic health.
    Keywords:  adaptations; cardiometabolic health; exercise; exercise physiology; exercise signaling; metabolism; multi-tissue
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.008
  28. Mol Cell. 2023 Dec 29. pii: S1097-2765(23)01031-6. [Epub ahead of print]
    Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
    Sabine Poerschke, Silke Oeljeklaus, Luis Daniel Cruz-Zaragoza, Alexander Schenzielorz, Drishan Dahal, Hauke Sven Hillen, Hirak Das, Laura Sophie Kremer, Anusha Valpadashi, Mirjam Breuer, Johannes Sattmann, Ricarda Richter-Dennerlein, Bettina Warscheid, Sven Dennerlein, Peter Rehling.
      Cellular proteostasis requires transport of polypeptides across membranes. Although defective transport processes trigger cytosolic rescue and quality control mechanisms that clear translocases and membranes from unproductive cargo, proteins that are synthesized within mitochondria are not accessible to these mechanisms. Mitochondrial-encoded proteins are inserted cotranslationally into the inner membrane by the conserved insertase OXA1L. Here, we identify TMEM126A as a OXA1L-interacting protein. TMEM126A associates with mitochondrial ribosomes and translation products. Loss of TMEM126A leads to the destabilization of mitochondrial translation products, triggering an inner membrane quality control process, in which newly synthesized proteins are degraded by the mitochondrial iAAA protease. Our data reveal that TMEM126A cooperates with OXA1L in protein insertion into the membrane. Upon loss of TMEM126A, the cargo-blocked OXA1L insertase complexes undergo proteolytic clearance by the iAAA protease machinery together with its cargo.
    Keywords:  mitochondria; mitochondrial quality control; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.013
  29. Immunity. 2024 Jan 09. pii: S1074-7613(23)00540-X. [Epub ahead of print]57(1): 14-27
    Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation.
    Mohammad Arifuzzaman, Nicholas Collins, Chun-Jun Guo, David Artis.
      Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently alter immune responses in health and disease. We discuss how specific dietary components and metabolites can be either pro-inflammatory or anti-inflammatory in a context- and tissue-dependent manner during infection, chronic inflammation, and cancer. Together, these studies emphasize the influence of diet-microbiota crosstalk on immune regulation that will have a significant impact on precision nutrition approaches and therapeutic interventions for managing inflammation, infection, and cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.009
  30. Indian J Cancer. 2024 Jan 04.
    Succinate dehydrogenase deficient renal cell carcinoma: A case report of an uncommon renal cancer.
    Duhita Kodare, Santosh Menon, Gagan Prakash, Sangeeta Desai.
       ABSTRACT: Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC) is a rare type of renal cancer with distinct morphological features and diagnostic immunohistochemistry characterized by the absence of SDH immunostaining. The pathologists and the clinician need to be aware of this entity in view of their indolent course in most cases. We present here the first case from India of SDHB-deficient RCC.
    DOI:  https://doi.org/10.4103/ijc.ijc_801_21
  31. bioRxiv. 2023 Dec 21. pii: 2023.12.20.572593. [Epub ahead of print]
    Unexpected roles for AMPK in suppression of autophagy and reactivation of mTORC1 signaling during prolonged amino acid deprivation.
    Dubek Kazyken, Sydney G Dame, Claudia Wang, Maxwell Wadley, Diane C Fingar.
      Amino acid withdrawal suppresses mTORC1 signaling rapidly, which initiates macroautophagy (herein, autophagy). Prolonged amino acid deprivation, however, leads to partial reactivation of mTORC1 due to the liberation of free amino acids by autophagic proteolysis. We observed impaired reactivation of mTORC1 signaling and increased apoptotic cell death upon prolonged amino acid withdrawal in cells lacking the AMPKα1/α2 catalytic subunits. These findings align well with the role of AMPK in promoting cell survival during energetic stress but oppose the well-documented inhibitory action of AMPK toward mTORC1. AMPK-mediated reactivation of mTORC1 during prolonged amino acid deprivation could be explained, however, if AMPK were required for autophagy. Indeed, a prevailing view posits that activation of AMPK by glucose withdrawal promotes autophagy and mitophagy through multisite phosphorylation of ULK1. When we examined the role of AMPK in autophagy induced by amino acid deprivation, however, we found unexpectedly that autophagy remained unimpaired in cells lacking AMPK α1/α2, as monitored by several autophagic readouts in several cell lines. Moreover, the absence of AMPK increased ULK1 signaling, LC3b lipidation, and lysosomal acidity, and the phosphorylation of ULK1 S555 (an AMPK site proposed to induce autophagy) decreased upon amino acid withdrawal or pharmacological mTORC1 inhibition. In addition, activation of AMPK with compound 991, glucose deprivation, or AICAR blunted basal and amino acid withdrawal-induced autophagy. Together our results demonstrate that AMPK suppresses rather than promotes autophagy and supports mTORC1 signaling during prolonged amino acid deprivation, revealing unexpected roles for AMPK in control of these processes.
    DOI:  https://doi.org/10.1101/2023.12.20.572593
  32. Cancer Discov. 2024 Jan 10.
    Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer.
    Yi Bei, Luca Brame, Marieluise Kirchner, Raphaela Fritsche-Guenther, Severine Kunz, Animesh Bhattacharya, Mara-Camelia Rusu, Dennis Gurgen, Frank P B Dubois, Julia K C Koppke, Jutta Proba, Nadine Wittstruck, Olga Alexandra Sidorova, Rocío Chamorro Gonzalez, Heathcliff Dorado Garcia, Lotte Bruckner, Robin Xu, Madalina Giurgiu, Elias Rodriguez-Fos, Qinghao Yu, Bastiaan Spanjaard, Richard P Koche, Clemens A Schmitt, Johannes H Schulte, Angelika Eggert, Kerstin Haase, Jennifer Kirwan, Anja Ih Hagemann, Philipp Mertins, Jan R Dorr, Anton G Henssen.
      DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger co-amplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger co-amplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that co-amplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency to the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked co-amplification of a passenger gene and an oncogene can result in collateral vulnerabilities.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1189
  33. Nat Commun. 2024 Jan 11. 15(1): 220
    Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol.
    Haruka Kemmoku, Kanoko Takahashi, Kojiro Mukai, Toshiki Mori, Koichiro M Hirosawa, Fumika Kiku, Yasunori Uchida, Yoshihiko Kuchitsu, Yu Nishioka, Masaaki Sawa, Takuma Kishimoto, Kazuma Tanaka, Yasunari Yokota, Hiroyuki Arai, Kenichi G N Suzuki, Tomohiko Taguchi.
      Stimulator of interferon genes (STING) is critical for the type I interferon response to pathogen- or self-derived DNA in the cytosol. STING may function as a scaffold to activate TANK-binding kinase 1 (TBK1), but direct cellular evidence remains lacking. Here we show, using single-molecule imaging of STING with enhanced time resolutions down to 5 ms, that STING becomes clustered at the trans-Golgi network (about 20 STING molecules per cluster). The clustering requires STING palmitoylation and the Golgi lipid order defined by cholesterol. Single-molecule imaging of TBK1 reveals that STING clustering enhances the association with TBK1. We thus provide quantitative proof-of-principle for the signaling STING scaffold, reveal the mechanistic role of STING palmitoylation in the STING activation, and resolve the long-standing question of the requirement of STING translocation for triggering the innate immune signaling.
    DOI:  https://doi.org/10.1038/s41467-023-44317-5
  34. Nat Chem Biol. 2024 Jan 11.
    Ironing out the mitochondria.
    Junsheng Chen, Tadashi Makio, Thomas Simmen.
      
    DOI:  https://doi.org/10.1038/s41589-023-01509-w
  35. Trends Pharmacol Sci. 2024 Jan 10. pii: S0165-6147(23)00261-4. [Epub ahead of print]
    Tumor iron homeostasis and immune regulation.
    Yan-Yu Zhang, Yi Han, Wen-Ning Li, Rui-Hua Xu, Huai-Qiang Ju.
      Abnormal iron metabolism has long been regarded as a key metabolic hallmark of cancer. As a critical cofactor, iron contributes to tumor progression by participating in various processes such as mitochondrial electron transport, gene regulation, and DNA synthesis or repair. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism between tumor cells and immune cells, which may affect both innate and adaptive immune responses. In this review, we discuss the current understanding of the regulatory networks of iron metabolism between cancer cells and immune cells and how they contribute to antitumor immunity, and we analyze potential therapeutics targeting iron metabolism. Also, we highlight several key challenges and describe potential therapeutic approaches for future investigations.
    Keywords:  adaptive immune; antitumor immunity; innate immune; iron metabolism
    DOI:  https://doi.org/10.1016/j.tips.2023.12.003
  36. Nat Rev Cancer. 2024 Jan 10.
    Sex affects cancer genomes.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-024-00663-0
  37. Immunity. 2024 Jan 09. pii: S1074-7613(23)00539-3. [Epub ahead of print]57(1): 3-5
    Kidney macrophages tap the stream.
    Pedro H V Saavedra, Justin S A Perry.
      Tissue-resident macrophages are essential for maintaining organismal homeostasis, but the precise mechanisms that macrophages use to perform this function are not fully understood. In this issue of Immunity, He et al. demonstrate that renal macrophages surveil and sample urine particles, ensuring optimal collecting duct flow and preventing kidney stone development.
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.008
  38. Nat Cell Biol. 2024 Jan 12.
    Cell origin of BRCA2-mutant breast cancer.
    Jiahui Xu, Suling Liu.
      
    DOI:  https://doi.org/10.1038/s41556-023-01322-6
  39. Aging Cell. 2024 Jan 11. e14082
    Age-regulated cycling metabolites are relevant for behavior.
    Jessica E Schwarz, Arjun Sengupta, Camilo Guevara, Annika F Barber, Cynthia T Hsu, Shirley L Zhang, Aalim Weljie, Amita Sehgal.
      Circadian cycles of sleep:wake and gene expression change with age in all organisms examined. Metabolism is also under robust circadian regulation, but little is known about how metabolic cycles change with age and whether these contribute to the regulation of behavioral cycles. To address this gap, we compared cycling of metabolites in young and old Drosophila and found major age-related variations. A significant model separated the young metabolic profiles by circadian timepoint, but could not be defined for the old metabolic profiles due to the greater variation in this dataset. Of the 159 metabolites measured in fly heads, we found 17 that cycle by JTK analysis in young flies and 17 in aged. Only four metabolites overlapped in the two groups, suggesting that cycling metabolites are distinct in young and old animals. Among our top cyclers exclusive to young flies were components of the pentose phosphate pathway (PPP). As the PPP is important for buffering reactive oxygen species, and overexpression of glucose-6-phosphate dehydrogenase (G6PD), a key component of the PPP, was previously shown to extend lifespan in Drosophila, we asked if this manipulation also affects sleep:wake cycles. We found that overexpression in circadian clock neurons decreases sleep in association with an increase in cellular calcium and mitochondrial oxidation, suggesting that altering PPP activity affects neuronal activity. Our findings elucidate the importance of metabolic regulation in maintaining patterns of neural activity, and thereby sleep:wake cycles.
    Keywords:   Drosophila ; aging; lipidomics; metabolomics; neuronal function; sleep
    DOI:  https://doi.org/10.1111/acel.14082
  40. Philos Trans R Soc Lond B Biol Sci. 2024 Feb 26. 379(1896): 20220498
    Consequences of the cost of living: is variation in metabolic rate evolutionarily significant?
    Amanda K Pettersen, Neil B Metcalfe.
      
    Keywords:  evolution; heritability; metabolism; pace of life; selection
    DOI:  https://doi.org/10.1098/rstb.2022.0498
  41. Mol Neurobiol. 2024 Jan 06.
    The Untargeted Metabolomics Reveals Differences in Energy Metabolism in Patients with Different Subtypes of Ischemic Stroke.
    Xi Li, Jiaxin Li, Fang Yu, Xianjing Feng, Yunfang Luo, Zeyu Liu, Tingting Zhao, Jian Xia.
       AIMS: Ischemic stroke (IS) is the most common subtype of stroke. The risk factors and pathogenesis of IS are complex and varied due to different subtypes. Therefore, we used metabolomics technology to investigate the biomarkers and potential pathophysiological mechanisms of different subtypes of IS.
    METHODS: We included 126 IS patients and divided them into two groups based on the TOAST classification: large-artery atherosclerosis (LAA) group (n = 87) and small-vessel occlusion (SVO) group (n = 39). Plasma metabolomics analysis was performed using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to identify metabolic profiles in LAA and SVO subtype IS patients and to determine metabolic differences between patients with the two subtypes of IS.
    RESULTS: We identified 26 differential metabolites between LAA and SVO subtype IS. A multiple prediction model based on the plasm metabolites had good predictive ability for IS subtyping (AUC = 0.822, accuracy = 77.8%), with 12,13-DHOME being the most important differential metabolite in the model. The differential metabolic pathways between the two subtypes of IS patients included tricarboxylic acid (TCA) cycle, alanine, aspartate and glutamate metabolism, and pyruvate metabolism, mainly focused on energy metabolism.
    CONCLUSION: 12,13-DHOME emerged as the primary discriminatory metabolite between LAA and SVO subtypes of IS. In LAA subtype IS patients, energy metabolism, encompassing pyruvate metabolism and the TCA cycle, exhibited lower activity levels when compared to patients with the SVO subtype IS. The utilization of targeted metabolomics holds the potential to improve diagnostic accuracy for distinguishing stroke subtypes.
    Keywords:  12, 13-DHOME; Ischemic stroke; Large-artery atherosclerosis; Metabolomics; Small-vessel occlusion
    DOI:  https://doi.org/10.1007/s12035-023-03884-w
  42. NPJ Aging. 2024 Jan 12. 10(1): 5
    Cholesterol biosynthetic pathway induces cellular senescence through ERRα.
    Dorian V Ziegler, Joanna Czarnecka-Herok, Mathieu Vernier, Charlotte Scholtes, Clara Camprubi, Anda Huna, Amélie Massemin, Audrey Griveau, Christelle Machon, Jérôme Guitton, Jennifer Rieusset, Arnaud M Vigneron, Vincent Giguère, Nadine Martin, David Bernard.
      Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate pathway-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes the transcriptional activity of ERRα that could lead to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis or level in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.
    DOI:  https://doi.org/10.1038/s41514-023-00128-y
  43. Am J Physiol Cell Physiol. 2024 Jan 08.
    Ketone Bodies in Cell Physiology and Cancer.
    Giacomo Giuliani, Valter D Longo.
      Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' post-translational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration. We also concentrate on KBs and cancer, given the extensive evidence that dietary approaches inducing ketosis, including Fasting Mimicking Diets (FMDs) and KDs, can prevent and affect tumor progression.
    Keywords:  cancer; fasting mimicking diet; ketone bodies; tumor metabolism; ß-hydroxybutyrate
    DOI:  https://doi.org/10.1152/ajpcell.00441.2023
  44. Nat Commun. 2024 Jan 10. 15(1): 433
    The chromatin landscape of healthy and injured cell types in the human kidney.
    Kidney Precision Medicine Project (KPMP)
      There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney's active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.
    DOI:  https://doi.org/10.1038/s41467-023-44467-6
  45. Mol Oncol. 2024 Jan 12.
    Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.
    Marc Pujalte-Martin, Amine Belaïd, Simon Bost, Michel Kahi, Pascal Peraldi, Matthieu Rouleau, Nathalie M Mazure, Frédéric Bost.
      Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.
    Keywords:  IACS-010759; cancer; clinical trial; immunometabolism; metformin; microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.13583
  46. Nat Commun. 2024 Jan 08. 15(1): 371
    Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice.
    Ming Shen Tham, Denny L Cottle, Allara K Zylberberg, Kieran M Short, Lynelle K Jones, Perkin Chan, Sarah E Conduit, Jennifer M Dyson, Christina A Mitchell, Ian M Smyth.
      Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA's role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT.
    DOI:  https://doi.org/10.1038/s41467-023-44410-9
  47. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01034-1. [Epub ahead of print]
    A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.
    Xu Wang, Sheng-Qiao Fu, Xiao Yuan, Feng Yu, Qian Ji, Hao-Wen Tang, Rong-Kun Li, Shan Huang, Pei-Qi Huang, Wei-Ting Qin, Hao Zuo, Chang Du, Lin-Li Yao, Hui Li, Jun Li, Dong-Xue Li, Yan Yang, Shu-Yu Xiao, Aziguli Tulamaiti, Xue-Feng Wang, Chun-Hua Dai, Xu Zhang, Shu-Heng Jiang, Li-Peng Hu, Xue-Li Zhang, Zhi-Gang Zhang.
      Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.
    Keywords:  5-HT; CD8(+) T cell; GAPDH; glycolysis; post-translational modification; serotonin; serotonylation; tumor immunity
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.015
  48. J Cell Sci. 2024 Jan 01. pii: jcs260986. [Epub ahead of print]137(1):
    Cristae shaping and dynamics in mitochondrial function.
    Claire Caron, Giulia Bertolin.
      Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.
    Keywords:  Cristae; Cristae dynamics; High-content approaches; Mitochondria; Quantitative microscopy
    DOI:  https://doi.org/10.1242/jcs.260986
  49. J Gen Physiol. 2024 Feb 05. pii: e202313451. [Epub ahead of print]156(2):
    Electro-metabolic signaling.
    Thomas A Longden, W Jonathan Lederer.
      Precise matching of energy substrate delivery to local metabolic needs is essential for the health and function of all tissues. Here, we outline a mechanistic framework for understanding this critical process, which we refer to as electro-metabolic signaling (EMS). All tissues exhibit changes in metabolism over varying spatiotemporal scales and have widely varying energetic needs and reserves. We propose that across tissues, common signatures of elevated metabolism or increases in energy substrate usage that exceed key local thresholds rapidly engage mechanisms that generate hyperpolarizing electrical signals in capillaries that then relax contractile elements throughout the vasculature to quickly adjust blood flow to meet changing needs. The attendant increase in energy substrate delivery serves to meet local metabolic requirements and thus avoids a mismatch in supply and demand and prevents metabolic stress. We discuss in detail key examples of EMS that our laboratories have discovered in the brain and the heart, and we outline potential further EMS mechanisms operating in tissues such as skeletal muscle, pancreas, and kidney. We suggest that the energy imbalance evoked by EMS uncoupling may be central to cellular dysfunction from which the hallmarks of aging and metabolic diseases emerge and may lead to generalized organ failure states-such as diverse flavors of heart failure and dementia. Understanding and manipulating EMS may be key to preventing or reversing these dysfunctions.
    DOI:  https://doi.org/10.1085/jgp.202313451
  50. Philos Trans R Soc Lond B Biol Sci. 2024 Feb 26. 379(1896): 20220482
    Tissue-specific metabolic enzyme levels covary with whole-animal metabolic rates and life-history loci via epistatic effects.
    Jenni M Prokkola, Kuan Kiat Chew, Katja Anttila, Katja S Maamela, Atakan Yildiz, Eirik R Åsheim, Craig R Primmer, Tutku Aykanat.
      Metabolic rates, including standard (SMR) and maximum (MMR) metabolic rate have often been linked with life-history strategies. Variation in context- and tissue-level metabolism underlying SMR and MMR may thus provide a physiological basis for life-history variation. This raises a hypothesis that tissue-specific metabolism covaries with whole-animal metabolic rates and is genetically linked to life history. In Atlantic salmon (Salmo salar), variation in two loci, vgll3 and six6, affects life history via age-at-maturity as well as MMR. Here, using individuals with known SMR and MMR with different vgll3 and six6 genotype combinations, we measured proxies of mitochondrial density and anaerobic metabolism, i.e. maximal activities of the mitochondrial citrate synthase (CS) and lactate dehydrogenase (LDH) enzymes, in four tissues (heart, intestine, liver, white muscle) across low- and high-food regimes. We found enzymatic activities were related to metabolic rates, mainly SMR, in the intestine and heart. Individual loci were not associated with the enzymatic activities, but we found epistatic effects and genotype-by-environment interactions in CS activity in the heart and epistasis in LDH activity in the intestine. These effects suggest that mitochondrial density and anaerobic capacity in the heart and intestine may partly mediate variation in metabolic rates and life history via age-at-maturity. This article is part of the theme issue 'The evolutionary significance of variation in metabolic rates'.
    Keywords:  energy allocation; epistasis; food restriction; glycolysis; mitochondria; salmonid
    DOI:  https://doi.org/10.1098/rstb.2022.0482
  51. Philos Trans R Soc Lond B Biol Sci. 2024 Feb 26. 379(1896): 20220491
    Estimating the relationship between fitness and metabolic rate: which rate should we use?
    Hayley Cameron, Dustin Marshall.
      As physiologists seek to better understand how and why metabolism varies, they have focused on how metabolic rate covaries with fitness-that is, selection. Evolutionary biologists have developed a sophisticated framework for exploring selection, but there are particular challenges associated with estimating selection on metabolic rate owing to its allometric relationship with body mass. Most researchers estimate selection on mass and absolute metabolic rate; or selection on mass and mass-independent metabolic rate (MIMR)-the residuals generated from a nonlinear regression. These approaches are sometimes treated as synonymous: their coefficients are often interpreted in the same way. Here, we show that these approaches are not equivalent because absolute metabolic rate and MIMR are different traits. We also show that it is difficult to make sound biological inferences about selection on absolute metabolic rate because its causal relationship with mass is enigmatic. By contrast, MIMR requires less-desirable statistical practices (i.e. residuals as a predictor), but provides clearer causal pathways. Moreover, we argue that estimates of selection on MIMR have more meaningful interpretations for physiologists interested in the drivers of variation in metabolic allometry. This article is part of the theme issue 'The evolutionary significance of variation in metabolic rates'.
    Keywords:  absolute metabolic rate; evolutionary physiology; mass-independent metabolic rate; metabolic scaling; performance; selection analysis
    DOI:  https://doi.org/10.1098/rstb.2022.0491
  52. Science. 2024 Jan 12. 383(6679): 190-200
    Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape.
    Pankaj Sharma, Xiaolong Zhang, Kevin Ly, Ji Hyung Kim, Qi Wan, Jessica Kim, Mumeng Lou, Lisa Kain, Luc Teyton, Florian Winau.
      Tumors develop strategies to evade immunity by suppressing antigen presentation. In this work, we show that prosaposin (pSAP) drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor dendritic cells (DCs) leads to cancer immune escape. We found that lysosomal pSAP and its single-saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, transforming growth factor-β (TGF-β) induced hyperglycosylation of pSAP and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. pSAP hyperglycosylation was also observed in tumor-associated DCs from melanoma patients, and reconstitution with pSAP rescued activation of tumor-infiltrating T cells. Targeting DCs with recombinant pSAP triggered tumor protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of pSAP in tumor immunity and may support its role in immunotherapy.
    DOI:  https://doi.org/10.1126/science.adg1955
  53. Clin Transl Med. 2024 Jan;14(1): e1533
    A novel computational tool for tracking cancer energy hijacking from immune cells.
    Hongyi Zhang, Bo Li.
      Recent studies revealed a new biological process that malignant cancer cells hijack mitochondria from nearby T cells, providing another potential mechanism for immune evasion. We further confirmed this process at the single-cell genomic level through MERCI, a novel algorithm for tracking mitochondrial (MT) transfer. Applied to human cancer samples, MERCI identified a new cancer phenotype linked to MT hijacking, correlating with rapid tumour proliferation and poor patient survival. This discovery offers insights into the limitations of current cancer immunotherapies and suggests new therapeutic avenues targeting MT transfer to enhance cancer treatment efficacy.
    Keywords:  Deconvolution; Mitochondrial Transfer; Tumor-immune Interaction; single-cell genomics
    DOI:  https://doi.org/10.1002/ctm2.1533
  54. Nat Methods. 2024 Jan 08.
    Unsupervised and supervised discovery of tissue cellular neighborhoods from cell phenotypes.
    Yuxuan Hu, Jiazhen Rong, Yafei Xu, Runzhi Xie, Jacqueline Peng, Lin Gao, Kai Tan.
      It is poorly understood how different cells in a tissue organize themselves to support tissue functions. We describe the CytoCommunity algorithm for the identification of tissue cellular neighborhoods (TCNs) based on cell phenotypes and their spatial distributions. CytoCommunity learns a mapping directly from the cell phenotype space to the TCN space using a graph neural network model without intermediate clustering of cell embeddings. By leveraging graph pooling, CytoCommunity enables de novo identification of condition-specific and predictive TCNs under the supervision of sample labels. Using several types of spatial omics data, we demonstrate that CytoCommunity can identify TCNs of variable sizes with substantial improvement over existing methods. By analyzing risk-stratified colorectal and breast cancer data, CytoCommunity revealed new granulocyte-enriched and cancer-associated fibroblast-enriched TCNs specific to high-risk tumors and altered interactions between neoplastic and immune or stromal cells within and between TCNs. CytoCommunity can perform unsupervised and supervised analyses of spatial omics maps and enable the discovery of condition-specific cell-cell communication patterns across spatial scales.
    DOI:  https://doi.org/10.1038/s41592-023-02124-2
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