bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023‒06‒18
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
  2. Mitochondria: at the crossroads between mechanobiology and cell metabolism.
  3. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
  4. Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation.
  5. Pancreatic cancer epigenetics: adaptive metabolism reprograms starving primary tumors for widespread metastatic outgrowth.
  6. Metabolism along the life journey of T cells.
  7. Aging Disrupts Circadian Rhythms in Mouse Liver Mitochondria.
  8. Autophagy fuels mitochondrial function through regulation of iron metabolism in pancreatic cancer.
  9. Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals.
  10. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.
  11. A mitochondrial iron-responsive pathway regulated by DELE1.
  12. Mutant IDH in Gliomas: Role in Cancer and Treatment Options.
  13. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
  14. Genetic perturbation of AMP biosynthesis extends lifespan and restores metabolic health in a naturally short-lived vertebrate.
  15. mTOR Regulation of N-Myc Downstream Regulated 1 (NDRG1) Phosphorylation in Clear Cell Renal Cell Carcinoma.
  16. Constitutive Expression of Hif2α Confers Acute O2 Sensitivity to Carotid Body Glomus Cells.
  17. Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation.
  18. MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma.
  19. Itaconate trims the fat.
  20. Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination.
  21. PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
  22. Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.
  23. Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".
  24. Vital role of SHMT2 in diverse disease.
  25. Monitoring lysosomal acidity.
  26. Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.
  27. Acetate controls endothelial-to-mesenchymal transition.
  28. Yeast increases glycolytic flux to support higher growth rates accompanied by decreased metabolite regulation and lower protein phosphorylation.
  29. Mapping a comprehensive targetome of glycolytic metabolites in cancer cells.
  30. A convolutional neural network STIFMap reveals associations between stromal stiffness and EMT in breast cancer.
  31. Regulation of Mitochondrial Permeability Transition Pore Opening by Monovalent Cations in Liver Mitochondria.
  32. Sources and Sinks of Serine in Nutrition, Health, and Disease.
  33. Carnitine o-octanoyltransferase (CROT) is a p53 target that promotes oxidative metabolism and cell survival following nutrient starvation.
  34. Cancer genomes tolerate deleterious coding mutations through somatic copy number amplifications of wild-type regions.
  35. Taurine supplement makes animals live longer - what it means for people is unclear.
  36. Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
  37. Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution.
  38. Juneteenth in STEMM and the barriers to equitable science.
  39. Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease in male mice.
  40. Pan-cancer atlas of intratumour heterogeneity.
  41. Genome expansion by a CRISPR trimmer-integrase.
  42. Regulation of systemic metabolism by tissue-resident immune cell circuits.
  1. Redox Biol. 2023 Jun 04. pii: S2213-2317(23)00160-X. [Epub ahead of print]64 102759
    The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
    Anna Weiser, Aurélie Hermant, Flavien Bermont, Federico Sizzano, Sonia Karaz, Pilar Alvarez-Illera, Jaime Santo-Domingo, Vincenzo Sorrentino, Jerome N Feige, Umberto De Marchi.
      Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.
    Keywords:  C. elegans; Calcium signaling; MCU; Mitochondria; Redox biology; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2023.102759
  2. Biol Cell. 2023 Jun 16.
    Mitochondria: at the crossroads between mechanobiology and cell metabolism.
    Émilie Su, Catherine Villard, Jean-Baptiste Manneville.
      Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their reciprocal regulation has been increasingly acknowledged in recent years: external physical and mechanical cues entail metabolic changes, which in return regulate cell mechanosensing and mechanotransduction. Since mitochondria are pivotal regulators of metabolism, we review here the reciprocal links between mitochondrial morphodynamics, mechanics and metabolism. Mitochondria are highly dynamic organelles which sense and integrate mechanical, physical and metabolic cues to adapt their morphology, the organization of their network and their metabolic functions. While some of the links between mitochondrial morphodynamics, mechanics and metabolism are already well established, others are still poorly documented and open new fields of research. First, cell metabolism is known to correlate with mitochondrial morphodynamics. For instance, mitochondrial fission, fusion and cristae remodeling allow the cell to fine-tune its energy production through the contribution of mitochondrial oxidative phosphorylation and cytosolic glycolysis. Second, mechanical cues and alterations in mitochondrial mechanical properties reshape and reorganize the mitochondrial network. Mitochondrial membrane tension emerges as a decisive physical property which regulates mitochondrial morphodynamics. However, the converse link hypothesizing a contribution of morphodynamics to mitochondria mechanics and/or mechanosensitivity has not yet been demonstrated. Third, we highlight that mitochondrial mechanics and metabolism are reciprocally regulated, although little is known about the mechanical adaptation of mitochondria in response to metabolic cues. Deciphering the links between mitochondrial morphodynamics, mechanics and metabolism still presents significant technical and conceptual challenges but is crucial both for a better understanding of mechanobiology and for potential novel therapeutic approaches in diseases such as cancer. This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondrial morphodynamics; cancer; cytoskeleton; glycolysis; mechanotransduction; membrane tension; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/boc.202300010
  3. Life Sci Alliance. 2023 Sep;pii: e202302127. [Epub ahead of print]6(9):
    Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
    Jun Yong Kim, Ilian Atanassov, Frederik Dethloff, Lara Kroczek, Thomas Langer.
      Mitochondrial dysfunction and cellular senescence are hallmarks of aging. However, the relationship between these two phenomena remains incompletely understood. In this study, we investigated the rewiring of mitochondria upon development of the senescent state in human IMR90 fibroblasts. Determining the bioenergetic activities and abundance of mitochondria, we demonstrate that senescent cells accumulate mitochondria with reduced OXPHOS activity, resulting in an overall increase of mitochondrial activities in senescent cells. Time-resolved proteomic analyses revealed extensive reprogramming of the mitochondrial proteome upon senescence development and allowed the identification of metabolic pathways that are rewired with different kinetics upon establishment of the senescent state. Among the early responding pathways, the degradation of branched-chain amino acid was increased, whereas the one carbon folate metabolism was decreased. Late-responding pathways include lipid metabolism and mitochondrial translation. These signatures were confirmed by metabolic flux analyses, highlighting metabolic rewiring as a central feature of mitochondria in cellular senescence. Together, our data provide a comprehensive view on the changes in mitochondrial proteome in senescent cells and reveal how the mitochondrial metabolism is rewired in senescent cells.
    DOI:  https://doi.org/10.26508/lsa.202302127
  4. Nat Chem Biol. 2023 Jun 12.
    Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation.
    Lulu Chen, Qi Zhou, Pingfeng Zhang, Wei Tan, Yingge Li, Ziwen Xu, Junfeng Ma, Gary M Kupfer, Yanxin Pei, Qibin Song, Huadong Pei.
      O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.
    DOI:  https://doi.org/10.1038/s41589-023-01354-x
  5. Cancer Metastasis Rev. 2023 Jun 15.
    Pancreatic cancer epigenetics: adaptive metabolism reprograms starving primary tumors for widespread metastatic outgrowth.
    Arnaldo J Franco Torres, Jeffrey Duryea, Oliver G McDonald.
      Pancreatic cancer is a paradigm for adaptation to extreme stress. That is because genetic drivers are selected during tissue injury with epigenetic imprints encoding wound healing responses. Ironically, epigenetic memories of trauma that facilitate neoplasia can also recreate past stresses to restrain malignant progression through symbiotic tumor:stroma crosstalk. This is best exemplified by positive feedback between neoplastic chromatin outputs and fibroinflammatory stromal cues that encase malignant glands within a nutrient-deprived desmoplastic stroma. Because epigenetic imprints are chemically encoded by nutrient-derived metabolites bonded to chromatin, primary tumor metabolism adapts to preserve malignant epigenetic fidelity during starvation. Despite these adaptations, stromal stresses inevitably awaken primordial drives to seek more hospitable climates. The invasive migrations that ensue facilitate entry into the metastatic cascade. Metastatic routes present nutrient-replete reservoirs that accelerate malignant progression through adaptive metaboloepigenetics. This is best exemplified by positive feedback between biosynthetic enzymes and nutrient transporters that saturate malignant chromatin with pro-metastatic metabolite byproducts. Here we present a contemporary view of pancreatic cancer epigenetics: selection of neoplastic chromatin under fibroinflammatory pressures, preservation of malignant chromatin during starvation stresses, and saturation of metastatic chromatin by nutritional excesses that fuel lethal metastasis.
    Keywords:  Cancer; Epigenetics; Metabolism; Metastasis; Pancreatic
    DOI:  https://doi.org/10.1007/s10555-023-10116-z
  6. Life Metab. 2023 Feb;pii: load002. [Epub ahead of print]2(1):
    Metabolism along the life journey of T cells.
    Min Peng, Ming O Li.
      T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation, which serves as an excellent example to dissect the metabolic basis of cell fate decisions. During the last decade, there has been an explosion of research into the metabolic control of T-cell responses. The roles of common metabolic pathways, including glycolysis, lipid metabolism, and mitochondrial oxidative phosphorylation, in T-cell responses have been well characterized, and their mechanisms of action are starting to emerge. In this review, we present several considerations for T-cell metabolism-focused research, while providing an overview of the metabolic control of T-cell fate decisions during their life journey. We try to synthesize principles that explain the causal relationship between cellular metabolism and T-cell fate decision. We also discuss key unresolved questions and challenges in targeting T-cell metabolism to treat disease.
    Keywords:  FAO; OXPHOS; T cells; acetyl-CoA; glycolysis; immunometabolism
    DOI:  https://doi.org/10.1093/lifemeta/load002
  7. Molecules. 2023 May 30. pii: 4432. [Epub ahead of print]28(11):
    Aging Disrupts Circadian Rhythms in Mouse Liver Mitochondria.
    Wei Xu, Xiaodong Li.
      The circadian clock regulates daily changes in behavioral, endocrine, and metabolic activities in mammals. Circadian rhythms in cellular physiology are significantly affected by aging. In particular, we previously found that aging has a profound impact on daily rhythms in mitochondrial functions in mouse liver, leading to increased oxidative stress. This is not due to molecular clock malfunctions in peripheral tissues in old mice, however, as robust clock oscillations are observed therein. Nonetheless, aging induces changes in gene expression levels and rhythms in peripheral and probably central tissues. In this article, we review recent findings on the roles of the circadian clock and the aging process in regulating mitochondrial rhythms and redox homeostasis. Chronic sterile inflammation is implicated in mitochondrial dysfunction and increased oxidative stress during aging. In particular, upregulation of the NADase CD38 by inflammation during aging contributes to mitochondrial dysregulation.
    Keywords:  aging; circadian rhythms; inflammatory response; peripheral clock; senescence
    DOI:  https://doi.org/10.3390/molecules28114432
  8. Autophagy. 2023 Jun 13. 1-2
    Autophagy fuels mitochondrial function through regulation of iron metabolism in pancreatic cancer.
    Subhadip Mukhopadhyay, Joel Encarnacion-Rosado, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of any cancer in the United States. Our previous work has shown that autophagy can promote PDAC progression. We recently established the importance of autophagy in regulating bioavailable iron to control mitochondrial metabolism in PDAC. We found that inhibition of autophagy in PDAC leads to mitochondrial dysfunction due to abrogation of succinate dehydrogenase complex iron sulfur subunit B (SDHB) expression. Additionally, we observed that cancer-associated fibroblasts (CAFs) can provide iron to autophagy-inhibited PDAC tumor cells, thereby increasing their resistance to autophagy inhibition. To impede such metabolic compensation, we used a low iron diet together with autophagy inhibition and demonstrated a significant improvement of tumor response in syngeneic PDAC models.Abbreviations: PDAC: Pancreatic ductal adenocarcinoma; CAFs: cancer-associated fibroblasts; SDHB: succinate dehydrogenase complex iron sulfur subunit B; ISCA1: iron sulfur cluster assembly protein 1; FPN: ferroportin; LIP: labile iron pool; FAC: ferric ammonium chloride; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation, IL6: interleukin 6; Fe-S: iron sulfur; ATP: adenosine triphosphate.
    Keywords:  Autophagy; cancer associated fibroblasts; iron metabolism; lysosome; mitochondria; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1080/15548627.2023.2223473
  9. J Vis Exp. 2023 May 19.
    Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals.
    Tenzin Tseyang, Jonathan Valeros, Paula Vo, Jessica B Spinelli.
      The flow of electrons in the mitochondrial electron transport chain (ETC) supports multifaceted biosynthetic, bioenergetic, and signaling functions in mammalian cells. As oxygen (O2) is the most ubiquitous terminal electron acceptor for the mammalian ETC, the O2 consumption rate is frequently used as a proxy for mitochondrial function. However, emerging research demonstrates that this parameter is not always indicative of mitochondrial function, as fumarate can be employed as an alternative electron acceptor to sustain mitochondrial functions in hypoxia. This article compiles a series of protocols that allow researchers to measure mitochondrial function independently of the O2 consumption rate. These assays are particularly useful when studying mitochondrial function in hypoxic environments. Specifically, we describe methods to measure mitochondrial ATP production, de novo pyrimidine biosynthesis, NADH oxidation by complex I, and superoxide production. In combination with classical respirometry experiments, these orthogonal and economical assays will provide researchers with a more comprehensive assessment of mitochondrial function in their system of interest.
    DOI:  https://doi.org/10.3791/65184
  10. Cell Metab. 2023 Jun 07. pii: S1550-4131(23)00185-7. [Epub ahead of print]
    Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.
    Miriam Ferrer, Nicholas Mourikis, Emma E Davidson, Sam O Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Qing Gao, Thomas R Flint, Lisa Young, Claire M Connell, Michael J Lukey, Marcus D Goncalves, Eileen P White, Ashok R Venkitaraman, Tobias Janowitz.
      Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.
    Keywords:  GDF-15; IL-6; NADPH; cachexia; cancer; corticosterone; ferroptosis; ketogenic diet; lipid peroxidation; steroid
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.008
  11. Mol Cell. 2023 Jun 15. pii: S1097-2765(23)00413-6. [Epub ahead of print]83(12): 2059-2076.e6
    A mitochondrial iron-responsive pathway regulated by DELE1.
    Yusuke Sekine, Ryan Houston, Eva-Maria Eckl, Evelyn Fessler, Derek P Narendra, Lucas T Jae, Shiori Sekine.
      The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.
    Keywords:  DELE1; HRI; LONP1; erythroid cells; integrated stress response; iron; mitochondria; mitochondrial import; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.031
  12. Cancers (Basel). 2023 May 23. pii: 2883. [Epub ahead of print]15(11):
    Mutant IDH in Gliomas: Role in Cancer and Treatment Options.
    Georgios Solomou, Alina Finch, Asim Asghar, Chiara Bardella.
      Altered metabolism is a common feature of many cancers and, in some cases, is a consequence of mutation in metabolic genes, such as the ones involved in the TCA cycle. Isocitrate dehydrogenase (IDH) is mutated in many gliomas and other cancers. Physiologically, IDH converts isocitrate to α-ketoglutarate (α-KG), but when mutated, IDH reduces α-KG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at elevated levels in IDH mutant tumours, and in the last decade, a massive effort has been made to develop small inhibitors targeting mutant IDH. In this review, we summarise the current knowledge about the cellular and molecular consequences of IDH mutations and the therapeutic approaches developed to target IDH mutant tumours, focusing on gliomas.
    Keywords:  cancer metabolism; gliomas; hydroxyglutarate; isocitrate dehydrogenase; oncometabolites
    DOI:  https://doi.org/10.3390/cancers15112883
  13. Cell Rep. 2023 Jun 12. pii: S2211-1247(23)00652-6. [Epub ahead of print]42(6): 112641
    Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
    Kiyoto Nishi, Akira Yoshii, Lauren Abell, Bo Zhou, Ricardo Frausto, Julia Ritterhoff, Timothy S McMillen, Ian Sweet, Yibin Wang, Chen Gao, Rong Tian.
      Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.
    Keywords:  CP: Metabolism; branched-chain amino acids; branched-chain keto acids; gluconeogenesis; mitochondrial pyruvate carrier; pyruvate
    DOI:  https://doi.org/10.1016/j.celrep.2023.112641
  14. Dev Cell. 2023 Jun 08. pii: S1534-5807(23)00248-4. [Epub ahead of print]
    Genetic perturbation of AMP biosynthesis extends lifespan and restores metabolic health in a naturally short-lived vertebrate.
    Gwendoline Astre, Tehila Atlan, Uri Goshtchevsky, Adi Oron-Gottesman, Margarita Smirnov, Kobi Shapira, Ariel Velan, Joris Deelen, Tomer Levy, Erez Y Levanon, Itamar Harel.
      During aging, the loss of metabolic homeostasis drives a myriad of pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex in mice have, so far, produced detrimental phenotypes. Here, as an alternative approach, we alter energy homeostasis by manipulating the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and extend the lifespan of heterozygous males. Next, we apply an integrated omics approach to show that metabolic functions are rejuvenated in old mutants, which also display a fasting-like metabolic profile and resistance to high-fat diet. At the cellular level, heterozygous cells exhibit enhanced nutrient sensitivity, reduced ATP levels, and AMPK activation. Finally, lifelong intermittent fasting abolishes the longevity benefits. Our findings suggest that perturbing AMP biosynthesis may modulate vertebrate lifespan and propose APRT as a promising target for promoting metabolic health.
    Keywords:  AMP biosynthesis; AMPK; APRT; CRISPR; aging; killifish; longevity; metabolism; nutrient sensing; sex differences
    DOI:  https://doi.org/10.1016/j.devcel.2023.05.015
  15. Int J Mol Sci. 2023 May 27. pii: 9364. [Epub ahead of print]24(11):
    mTOR Regulation of N-Myc Downstream Regulated 1 (NDRG1) Phosphorylation in Clear Cell Renal Cell Carcinoma.
    Anisha Valluri, Jessica Wellman, Chelsea L McCallister, Kathleen C Brown, Logan Lawrence, Rebecca Russell, James Jensen, James Denvir, Monica A Valentovic, Krista L Denning, Travis B Salisbury.
      The mechanistic target of rapamycin (mTOR) kinase is a component of two signaling complexes that are known as mTOR complex 1 (mTORC1) and mTORC2. We sought to identify mTOR-phosphorylated proteins that are differently expressed in clinically resected clear cell renal cell carcinoma (ccRCC) relative to pair-matched normal renal tissue. Using a proteomic array, we found N-Myc Downstream Regulated 1 (NDRG1) showed the greatest increase (3.3-fold) in phosphorylation (on Thr346) in ccRCC. This was associated with an increase in total NDRG1. RICTOR is a required subunit in mTORC2, and its knockdown decreased total and phospho-NDRG1 (Thr346) but not NDRG1 mRNA. The dual mTORC1/2 inhibitor, Torin 2, significantly reduced (by ~100%) phospho-NDRG1 (Thr346). Rapamycin is a selective mTORC1 inhibitor that had no effect on the levels of total NDRG1 or phospho-NDRG1 (Thr346). The reduction in phospho-NDRG1 (Thr346) due to the inhibition of mTORC2 corresponded with a decrease in the percentage of live cells, which was correlated with an increase in apoptosis. Rapamycin had no effect on ccRCC cell viability. Collectively, these data show that mTORC2 mediates the phosphorylation of NDRG1 (Thr346) in ccRCC. We hypothesize that RICTOR and mTORC2-mediated phosphorylation of NDRG1 (Thr346) promotes the viability of ccRCC cells.
    Keywords:  N-Myc Downstream Regulated 1; NDRG1; clear cell renal cell carcinoma; mTOR; mTORC1; mTORC2; proteomics
    DOI:  https://doi.org/10.3390/ijms24119364
  16. Adv Exp Med Biol. 2023 ;1427 153-162
    Constitutive Expression of Hif2α Confers Acute O2 Sensitivity to Carotid Body Glomus Cells.
    Olalla Colinas, Alejandro Moreno-Domínguez, Patricia Ortega-Sáenz, José López-Barneo.
      Acute oxygen (O2) sensing and adaptation to hypoxia are essential for physiological homeostasis. The prototypical acute O2 sensing organ is the carotid body, which contains chemosensory glomus cells expressing O2-sensitive K+ channels. Inhibition of these channels during hypoxia leads to cell depolarization, transmitter release, and activation of afferent sensory fibers terminating in the brain stem respiratory and autonomic centers. Focusing on recent data, here we discuss the special sensitivity of glomus cell mitochondria to changes in O2 tension due to Hif2α-dependent expression of several atypical mitochondrial electron transport chain subunits and enzymes. These are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. We report that ablation of Epas1 (the gene coding Hif2α) causes a selective downregulation of the atypical mitochondrial genes and a strong inhibition of glomus cell acute responsiveness to hypoxia. Our observations indicate that Hif2α expression is required for the characteristic metabolic profile of glomus cells and provide a mechanistic explanation for the acute O2 regulation of breathing.
    Keywords:  Acute oxygen sensing; Carotid body; Cell physiology; Glomus cells; Hypoxia; Mitochondrial subunit isoforms
    DOI:  https://doi.org/10.1007/978-3-031-32371-3_17
  17. J Theor Biol. 2023 Jun 14. pii: S0022-5193(23)00155-8. [Epub ahead of print] 111558
    Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation.
    Hong Qi, Yu-Song Yin, Zhi-Yong Yin, Xiang Li, Jian-Wei Shuai.
      Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 minutes, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-β production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.
    Keywords:  Apoptosis; Dynamic mechanism; Inflammation; Mitochondrial inner membrane permeabilization; Mitochondrial outer membrane permeabilization
    DOI:  https://doi.org/10.1016/j.jtbi.2023.111558
  18. Cancer Cell. 2023 Jun 12. pii: S1535-6108(23)00182-4. [Epub ahead of print]
    MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma.
    Yu Qian, Ana Galan-Cobo, Irene Guijarro, Minghao Dang, David Molkentine, Alissa Poteete, Fahao Zhang, Qi Wang, Jing Wang, Edwin Parra, Apekshya Panda, Jacy Fang, Ferdinandos Skoulidis, Ignacio I Wistuba, Svena Verma, Taha Merghoub, Jedd D Wolchok, Kwok-Kin Wong, Ralph J DeBerardinis, John D Minna, Natalie I Vokes, Catherine B Meador, Justin F Gainor, Linghua Wang, Alexandre Reuben, John V Heymach.
      Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.
    Keywords:  LKB1; MCT4; PD-1; T cell activation; immunotherapy resistance; lactate; lung adenocarcinoma; macrophage polarization; metabolism
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.015
  19. Nat Metab. 2023 Jun 12.
    Itaconate trims the fat.
    Rory Turner, Thekla Cordes, Martina Wallace.
      
    DOI:  https://doi.org/10.1038/s42255-023-00819-6
  20. Mol Cell. 2023 Jun 07. pii: S1097-2765(23)00382-9. [Epub ahead of print]
    Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination.
    Juan-Manuel Schvartzman, Grace Forsyth, Henry Walch, Walid Chatila, Angelo Taglialatela, Brian J Lee, Xiaolu Zhu, Steven Gershik, Francesco V Cimino, Anthony Santella, Kamal Menghrajani, Alberto Ciccia, Richard Koche, Francisco Sánchez-Vega, Shan Zha, Craig B Thompson.
      Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The effects of 2HG have been reported to sensitize IDH tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors. However, unlike PARP-inhibitor-sensitive BRCA1/2 tumors, which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to a heterochromatin-dependent slowing of DNA replication accompanied by increased replication stress and DNA double-strand breaks. This replicative stress manifests as replication fork slowing, but the breaks are repaired without a significant increase in mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-(ADP-ribosylation). Treatment with PARP inhibitors increases DNA replication but results in incomplete DNA repair. These findings demonstrate a role for PARP in the replication of heterochromatin and further validate PARP as a therapeutic target in IDH-mutant tumors.
    Keywords:  PARP; dioxygenase; heterochromatin; isocitrate dehydrogenase; oncometabolite; replication stress
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.026
  21. EMBO J. 2023 Jun 12. e113908
    PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
    Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.
    Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)
    DOI:  https://doi.org/10.15252/embj.2023113908
  22. Free Radic Biol Med. 2023 Jun 07. pii: S0891-5849(23)00430-6. [Epub ahead of print]
    Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.
    Patricia Sánchez-Pérez, Ana Mata, May-Kristin Torp, Elia López-Bernardo, Christina M Heiestad, Jan Magnus Aronsen, Antonio Molina-Iracheta, Luis J Jiménez-Borreguero, Pablo García-Roves, Ana S H Costa, Christian Frezza, Michael P Murphy, Kåre-Olav Stenslokken, Susana Cadenas.
      Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site IQ in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.
    Keywords:  Energy metabolism; Ischemia-reperfusion injury; Mitochondrial respiration; Mitochondrial structure; Oxidative stress; UCP3 (uncoupling protein 3)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.014
  23. Cell Rep. 2023 Jun 13. pii: S2211-1247(23)00643-5. [Epub ahead of print]42(6): 112632
    Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".
    Julia A Jones, Na Wei, Haissi Cui, Yi Shi, Guangsen Fu, Navin Rauniyar, Ryan Shapiro, Yosuke Morodomi, Nadine Berenst, Calin Dan Dumitru, Sachiko Kanaji, John R Yates, Taisuke Kanaji, Xiang-Lei Yang.
      Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.
    Keywords:  CP: Cell biology; CP: Molecular biology; aminoacyl-tRNA synthetase; cell survival; oxidative stress; stress response; transcriptional regulation; translation inhibition
    DOI:  https://doi.org/10.1016/j.celrep.2023.112632
  24. Biochem Biophys Res Commun. 2023 May 26. pii: S0006-291X(23)00697-6. [Epub ahead of print]671 160-165
    Vital role of SHMT2 in diverse disease.
    Wenqi Ma, Ronghan Liu, Kai Zhao, Jiangbo Zhong.
      One-carbon metabolism is essential for our human cells to carry out nucleotide synthesis, methylation, and reductive metabolism through one-carbon units, and these pathways ensure the high proliferation rate of cancer cells. Serine hydroxymethyltransferase 2 (SHMT2) is a key enzyme in one-carbon metabolism. This enzyme can convert serine into a one-carbon unit bound to tetrahydrofolate and glycine, ultimately supporting the synthesis of thymidine and purines and promoting the growth of cancer cells. Due to SHMT2's crucial role in the one-carbon cycle, it is ubiquitous in human cells and even in all organisms and highly conserved. Here, we summarize the impact of SHMT2 on the progression of various cancers to highlight its potential use in the development of cancer treatments.
    Keywords:  Cancer; One-carbon metabolism; Prognostic marker; SHMT2; Tumor growth
    DOI:  https://doi.org/10.1016/j.bbrc.2023.05.108
  25. Nat Chem Biol. 2023 Jun 15.
    Monitoring lysosomal acidity.
    Kangqiang Qiu, Zhiqi Tian, Jiajie Diao.
      
    DOI:  https://doi.org/10.1038/s41589-023-01348-9
  26. Blood Adv. 2023 Jun 14. pii: bloodadvances.2023010083. [Epub ahead of print]
    Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.
    Dheerendra Gupta, Ahmed Elwakiel, Satish Ranjan, Manish Kumar Pandey, Shruthi Krishnan, Saira Ambreen, Reinhard Henschler, Rajiv Rana, Maria Keller, Uta Ceglarek, Khurrum Shahzad, Shrey Kohli, Berend Isermann.
      A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. T-cell pre-incubation with aPC for 1 hour prior to transplantation increases FOXP3+ Tregs and reduces acute graft versus host disease (aGvHD) in mice, but the underlying mechanism remains unknown. As cellular metabolism modulates epigenetic gene regulation and plasticity in T-cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation and ex vivo using T-cells isolated from aGvHD mice without and with aPC preincubation or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of Th1-cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced TCA metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, while FOXP3 expression in splenic T-cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T-cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic marks, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010083
  27. Cell Metab. 2023 Jun 08. pii: S1550-4131(23)00203-6. [Epub ahead of print]
    Acetate controls endothelial-to-mesenchymal transition.
    Xiaolong Zhu, Yunyun Wang, Ioana Soaita, Heon-Woo Lee, Hosung Bae, Nabil Boutagy, Anna Bostwick, Rong-Mo Zhang, Caitlyn Bowman, Yanying Xu, Sophie Trefely, Yu Chen, Lingfeng Qin, William Sessa, George Tellides, Cholsoon Jang, Nathaniel W Snyder, Luyang Yu, Zoltan Arany, Michael Simons.
      Endothelial-to-mesenchymal transition (EndMT), a process initiated by activation of endothelial TGF-β signaling, underlies numerous chronic vascular diseases and fibrotic states. Once induced, EndMT leads to a further increase in TGF-β signaling, thus establishing a positive-feedback loop with EndMT leading to more EndMT. Although EndMT is understood at the cellular level, the molecular basis of TGF-β-driven EndMT induction and persistence remains largely unknown. Here, we show that metabolic modulation of the endothelium, triggered by atypical production of acetate from glucose, underlies TGF-β-driven EndMT. Induction of EndMT suppresses the expression of the enzyme PDK4, which leads to an increase in ACSS2-dependent Ac-CoA synthesis from pyruvate-derived acetate. This increased Ac-CoA production results in acetylation of the TGF-β receptor ALK5 and SMADs 2 and 4 leading to activation and long-term stabilization of TGF-β signaling. Our results establish the metabolic basis of EndMT persistence and unveil novel targets, such as ACSS2, for the potential treatment of chronic vascular diseases.
    Keywords:  ACSS2; ALK5; PDK4; acetate; acetyl-CoA; atherosclerosis; endfothelial cells; endothelial-to-mesenchymal transition; transforming growth factor beta signaling
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.010
  28. Proc Natl Acad Sci U S A. 2023 Jun 20. 120(25): e2302779120
    Yeast increases glycolytic flux to support higher growth rates accompanied by decreased metabolite regulation and lower protein phosphorylation.
    Min Chen, Tingting Xie, Huan Li, Yingping Zhuang, Jianye Xia, Jens Nielsen.
      Supply of Gibbs free energy and precursors are vital for cellular function and cell metabolism have evolved to be tightly regulated to balance their supply and consumption. Precursors and Gibbs free energy are generated in the central carbon metabolism (CCM), and fluxes through these pathways are precisely regulated. However, how fluxes through CCM pathways are affected by posttranslational modification and allosteric regulation remains poorly understood. Here, we integrated multi-omics data collected under nine different chemostat conditions to explore how fluxes in the CCM are regulated in the yeast Saccharomyces cerevisiae. We deduced a pathway- and metabolism-specific CCM flux regulation mechanism using hierarchical analysis combined with mathematical modeling. We found that increased glycolytic flux associated with an increased specific growth rate was accompanied by a decrease in flux regulation by metabolite concentrations, including the concentration of allosteric effectors, and a decrease in the phosphorylation level of glycolytic enzymes.
    Keywords:  Crabtree effect; metabolism; omics integration; yeast
    DOI:  https://doi.org/10.1073/pnas.2302779120
  29. Nat Chem Biol. 2023 Jun 15.
    Mapping a comprehensive targetome of glycolytic metabolites in cancer cells.
      
    DOI:  https://doi.org/10.1038/s41589-023-01366-7
  30. Nat Commun. 2023 Jun 15. 14(1): 3561
    A convolutional neural network STIFMap reveals associations between stromal stiffness and EMT in breast cancer.
    Connor Stashko, Mary-Kate Hayward, Jason J Northey, Neil Pearson, Alastair J Ironside, Johnathon N Lakins, Roger Oria, Marie-Anne Goyette, Lakyn Mayo, Hege G Russnes, E Shelley Hwang, Matthew L Kutys, Kornelia Polyak, Valerie M Weaver.
      Intratumor heterogeneity associates with poor patient outcome. Stromal stiffening also accompanies cancer. Whether cancers demonstrate stiffness heterogeneity, and if this is linked to tumor cell heterogeneity remains unclear. We developed a method to measure the stiffness heterogeneity in human breast tumors that quantifies the stromal stiffness each cell experiences and permits visual registration with biomarkers of tumor progression. We present Spatially Transformed Inferential Force Map (STIFMap) which exploits computer vision to precisely automate atomic force microscopy (AFM) indentation combined with a trained convolutional neural network to predict stromal elasticity with micron-resolution using collagen morphological features and ground truth AFM data. We registered high-elasticity regions within human breast tumors colocalizing with markers of mechanical activation and an epithelial-to-mesenchymal transition (EMT). The findings highlight the utility of STIFMap to assess mechanical heterogeneity of human tumors across length scales from single cells to whole tissues and implicates stromal stiffness in tumor cell heterogeneity.
    DOI:  https://doi.org/10.1038/s41467-023-39085-1
  31. Int J Mol Sci. 2023 May 25. pii: 9237. [Epub ahead of print]24(11):
    Regulation of Mitochondrial Permeability Transition Pore Opening by Monovalent Cations in Liver Mitochondria.
    Ekaterina S Kharechkina, Anna B Nikiforova, Alexey G Kruglov.
      The opening of the permeability transition pore (PTP) in mitochondria is a key event in the initiation of cell death in various pathologic states, including ischemia/reperfusion. The activation of K+ transport into mitochondria protects cells from ischemia/reperfusion. However, the role of K+ transport in PTP regulation is unclear. Here, we studied the role of K+ and other monovalent cations in the regulation of the PTP opening in an in vitro model. The registration of the PTP opening, membrane potential, Ca2+-retention capacity, matrix pH, and K+ transport was performed using standard spectral and electrode techniques. We found that the presence of all cations tested in the medium (K+, Na+, choline+, and Li+) strongly stimulated the PTP opening compared with sucrose. Several possible reasons for this were examined: the effect of ionic strength, the influx of cations through selective and non-selective channels and exchangers, the suppression of Ca2+/H+ exchange, and the influx of anions. The data obtained indicate that the mechanism of PTP stimulation by cations includes the suppression of K+/H+ exchange and acidification of the matrix, which facilitates the influx of phosphate. Thus, the K+/H+ exchanger and the phosphate carrier together with selective K+ channels compose a PTP regulatory triad, which might operate in vivo.
    Keywords:  K+ channels; K+/H+ exchanger; monovalent cations; permeability transition pore; phosphate carrier
    DOI:  https://doi.org/10.3390/ijms24119237
  32. Annu Rev Nutr. 2023 Jun 12.
    Sources and Sinks of Serine in Nutrition, Health, and Disease.
    Michal K Handzlik, Christian M Metallo.
      Amino acid dysregulation has emerged as an important driver of disease progression in various contexts. L-Serine lies at a central node of metabolism, linking carbohydrate metabolism, transamination, glycine, and folate-mediated one-carbon metabolism to protein synthesis and various downstream bioenergetic and biosynthetic pathways. L-Serine is produced locally in the brain but is sourced predominantly from glycine and one-carbon metabolism in peripheral tissues via liver and kidney metabolism. Compromised regulation or activity of L-serine synthesis and disposal occurs in the context of genetic diseases as well as chronic disease states, leading to low circulating L-serine levels and pathogenesis in the nervous system, retina, heart, and aging muscle. Dietary interventions in preclinical models modulate sensory neuropathy, retinopathy, tumor growth, and muscle regeneration. A serine tolerance test may provide a quantitative readout of L-serine homeostasis that identifies patients who may be susceptible to neuropathy or responsive to therapy. Expected final online publication date for the Annual Review of Nutrition, Volume 43 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-nutr-061021-022648
  33. J Biol Chem. 2023 Jun 10. pii: S0021-9258(23)01936-1. [Epub ahead of print] 104908
    Carnitine o-octanoyltransferase (CROT) is a p53 target that promotes oxidative metabolism and cell survival following nutrient starvation.
    Jack D Sanford, Derek Franklin, Gabriella A Grois, Aiwen Jin, Yanping Zhang.
      Whereas it is known that p53 broadly regulates cell metabolism, the specific activities that mediate this regulation remain partially understood. Here, we identified carnitine o-octanoyltransferase (CROT) as a p53 transactivation target that is upregulated by cellular stresses in a p53-dependent manner. CROT is a peroxisomal enzyme catalyzing very long-chain fatty acids (VLCFAs) conversion to medium chain fatty acids (MCFAs) that can be absorbed by mitochondria during β-oxidation. p53 induces CROT transcription through binding to consensus response elements in the 5'-UTR of CROT mRNA. Overexpression of wild type but not enzymatically inactive mutant CROT promotes mitochondrial oxidative respiration, while down-regulation of CROT inhibits mitochondrial oxidative respiration. Nutrient depletion induces p53-dependent CROT expression that facilitates cell growth and survival; in contrast cells deficient in CROT have blunted cell growth and reduced survival during nutrient depletion. Together, these data are consistent with a model where p53-regulated CROT expression allows cells to be more efficiently utilizing stored VLCFAs to survive nutrient depletion stresses.
    Keywords:  CROT; nutrient starvation; oxidative metabolism; p53
    DOI:  https://doi.org/10.1016/j.jbc.2023.104908
  34. Nat Commun. 2023 Jun 16. 14(1): 3594
    Cancer genomes tolerate deleterious coding mutations through somatic copy number amplifications of wild-type regions.
    Fabio Alfieri, Giulio Caravagna, Martin H Schaefer.
      Cancers evolve under the accumulation of thousands of somatic mutations and chromosomal aberrations. While most coding mutations are deleterious, almost all protein-coding genes lack detectable signals of negative selection. This raises the question of how tumors tolerate such large amounts of deleterious mutations. Using 8,690 tumor samples from The Cancer Genome Atlas, we demonstrate that copy number amplifications frequently cover haploinsufficient genes in mutation-prone regions. This could increase tolerance towards the deleterious impact of mutations by creating safe copies of wild-type regions and, hence, protecting the genes therein. Our findings demonstrate that these potential buffering events are highly influenced by gene functions, essentiality, and mutation impact and that they occur early during tumor evolution. We show how cancer type-specific mutation landscapes drive copy number alteration patterns across cancer types. Ultimately, our work paves the way for the detection of novel cancer vulnerabilities by revealing genes that fall within amplifications likely selected during evolution to mitigate the effect of mutations.
    DOI:  https://doi.org/10.1038/s41467-023-39313-8
  35. Nature. 2023 Jun 09.
    Taurine supplement makes animals live longer - what it means for people is unclear.
    Myriam Vidal Valero.
      
    Keywords:  Ageing; Metabolism; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-023-01910-4
  36. Sci Immunol. 2023 Jun 23. 8(84): eade7652
    Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
    Sung Hoon Baik, V Krishnan Ramanujan, Courtney Becker, Sarah Fett, David M Underhill, Andrea J Wolf.
      NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.
    DOI:  https://doi.org/10.1126/sciimmunol.ade7652
  37. Science. 2023 Jun 16. 380(6650): eadg0934
    Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution.
    Tzu-Chiao Lu, Maria Brbić, Ye-Jin Park, Tyler Jackson, Jiaye Chen, Sai Saroja Kolluru, Yanyan Qi, Nadja Sandra Katheder, Xiaoyu Tracy Cai, Seungjae Lee, Yen-Chung Chen, Niccole Auld, Chung-Yi Liang, Sophia H Ding, Doug Welsch, Samuel D'Souza, Angela Oliveira Pisco, Robert C Jones, Jure Leskovec, Eric C Lai, Hugo J Bellen, Liqun Luo, Heinrich Jasper, Stephen R Quake, Hongjie Li.
      Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterized 163 distinct cell types and performed an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further developed aging clock models to predict fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find distinctive cell type-specific aging patterns. This atlas provides a valuable resource for studying fundamental principles of aging in complex organisms.
    DOI:  https://doi.org/10.1126/science.adg0934
  38. Cell. 2023 Jun 08. pii: S0092-8674(23)00536-6. [Epub ahead of print]186(12): 2510-2517
    Juneteenth in STEMM and the barriers to equitable science.
    Alfred Mays, Angela Byars-Winston, Antentor Hinton, Andrea G Marshall, Annet Kirabo, Avery August, Bianca J Marlin, Blake Riggs, Blanton Tolbert, Celestine Wanjalla, Chad Womack, Chantell S Evans, Christopher Barnes, Chrystal Starbird, Clintoria Williams, Corey Reynolds, Cornelius Taabazuing, Craig E Cameron, Debra D Murray, Derek Applewhite, Derrick J Morton, Dexter Lee, Dionna W Williams, Donald Lynch, Donita Brady, Erin Lynch, Florentine U N Rutaganira, Gustavo M Silva, Haysetta Shuler, Ishmail Abdus Saboor, Jamaine Davis, Kafui Dzirasa, Latanya Hammonds-Odie, Loretta Reyes, Mariya T Sweetwyne, Melanie R McReynolds, Michael D L Johnson, Nathan A Smith, Nikea Pittman, Olujimi A Ajijola, Quinton Smith, Renã A S Robinson, Samantha C Lewis, Sandra A Murray, Sherilynn Black, Sonya E Neal, Stanley Andrisse, Steven Townsend, Steven M Damo, Theanne N Griffith, W Marcus Lambert, William M Clemons.
      We are 52 Black scientists. Here, we establish the context of Juneteenth in STEMM and discuss the barriers Black scientists face, the struggles they endure, and the lack of recognition they receive. We review racism's history in science and provide institutional-level solutions to reduce the burdens on Black scientists.
    Keywords:  Juneteenth; STEMM; diversity; scientific racism
    DOI:  https://doi.org/10.1016/j.cell.2023.05.016
  39. Nat Metab. 2023 Jun 12.
    Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease in male mice.
    Jonathan M Weiss, Erika M Palmieri, Marieli Gonzalez-Cotto, Ian A Bettencourt, Emily L Megill, Nathaniel W Snyder, Daniel W McVicar.
      Itaconate, the product of the decarboxylation of cis-aconitate, regulates numerous biological processes. We and others have revealed itaconate as a regulator of fatty acid β-oxidation, generation of mitochondrial reactive oxygen species and the metabolic interplay between resident macrophages and tumors. In the present study, we show that itaconic acid is upregulated in human non-alcoholic steatohepatitis and a mouse model of non-alcoholic fatty liver disease. Male mice deficient in the gene responsible for itaconate production (immunoresponsive gene (Irg)-1) have exacerbated lipid accumulation in the liver, glucose and insulin intolerance and mesenteric fat deposition. Treatment of mice with the itaconate derivative, 4-octyl itaconate, reverses dyslipidemia associated with high-fat diet feeding. Mechanistically, itaconate treatment of primary hepatocytes reduces lipid accumulation and increases their oxidative phosphorylation in a manner dependent upon fatty acid oxidation. We propose a model whereby macrophage-derived itaconate acts in trans upon hepatocytes to modulate the liver's ability to metabolize fatty acids.
    DOI:  https://doi.org/10.1038/s42255-023-00801-2
  40. Nat Rev Genet. 2023 Jun 14.
    Pan-cancer atlas of intratumour heterogeneity.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41576-023-00627-4
  41. Nature. 2023 Jun 14.
    Genome expansion by a CRISPR trimmer-integrase.
    Joy Y Wang, Owen T Tuck, Petr Skopintsev, Katarzyna M Soczek, Gary Li, Basem Al-Shayeb, Julia Zhou, Jennifer A Doudna.
      CRISPR-Cas adaptive immune systems capture DNA fragments from invading mobile genetic elements and integrate them into the host genome to provide a template for RNA-guided immunity1. CRISPR systems maintain genome integrity and avoid autoimmunity by distinguishing between self and non-self, a process for which the CRISPR/Cas1-Cas2 integrase is necessary but not sufficient2-5. In some microorganisms, the Cas4 endonuclease assists CRISPR adaptation6,7, but many CRISPR-Cas systems lack Cas48. Here we show here that an elegant alternative pathway in a type I-E system uses an internal DnaQ-like exonuclease (DEDDh) to select and process DNA for integration using the protospacer adjacent motif (PAM). The natural Cas1-Cas2/exonuclease fusion (trimmer-integrase) catalyses coordinated DNA capture, trimming and integration. Five cryo-electron microscopy structures of the CRISPR trimmer-integrase, visualized both before and during DNA integration, show how asymmetric processing generates size-defined, PAM-containing substrates. Before genome integration, the PAM sequence is released by Cas1 and cleaved by the exonuclease, marking inserted DNA as self and preventing aberrant CRISPR targeting of the host. Together, these data support a model in which CRISPR systems lacking Cas4 use fused or recruited9,10 exonucleases for faithful acquisition of new CRISPR immune sequences.
    DOI:  https://doi.org/10.1038/s41586-023-06178-2
  42. Immunity. 2023 Jun 13. pii: S1074-7613(23)00218-2. [Epub ahead of print]56(6): 1168-1186
    Regulation of systemic metabolism by tissue-resident immune cell circuits.
    Joey H Li, Matthew R Hepworth, Timothy E O'Sullivan.
      Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
    Keywords:  cell circuits; immunometabolism; metabolism; systems immunology; tissue homeostasis; tissue-resident
    DOI:  https://doi.org/10.1016/j.immuni.2023.05.001
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