bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022‒08‒28
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Glutamine metabolism mediates sensitivity to respiratory complex II inhibition in acute myeloid leukemia.
  2. Advances in measuring cancer cell metabolism with subcellular resolution.
  3. The histone deacetylases Rpd3 and Hst1 antagonistically regulate de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae.
  4. Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
  5. An Epigenetic Role of Mitochondria in Cancer.
  6. Cell death: All roads lead to mitochondria.
  7. Mitochondrial Ultrastructure and Activity Are Differentially Regulated by Glycolysis-, Krebs Cycle-, and Microbiota-Derived Metabolites in Monocytes.
  8. EATING YOUR OWN FAT TO STAY FIT: LIPOPHAGY SUSTAINS LYMPHANGIOGENESIS.
  9. Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.
  10. LIX1-mediated changes in mitochondrial metabolism control the fate of digestive mesenchyme-derived cells.
  11. Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease.
  12. β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveal their essential role as nutrient sensors for the KATP channel.
  13. MicroRNAs as Regulators of Cancer Cell Energy Metabolism.
  14. NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity.
  15. Glycerol-3-phosphate shuttle is a backup system securing metabolic flexibility in neurons.
  16. Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.
  17. Reverse and Forward Electron Flow-Induced H2O2 Formation Is Decreased in α-Ketoglutarate Dehydrogenase (α-KGDH) Subunit (E2 or E3) Heterozygote Knock Out Animals.
  18. Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.
  19. GPT2 Is Induced by Hypoxia-Inducible Factor (HIF)-2 and Promotes Glioblastoma Growth.
  20. Recent Progress in Analysis of Intermediary Metabolism by ex vivo 13 C NMR.
  21. Peroxisomal regulation of energy homeostasis: Effect on obesity and related metabolic disorders.
  22. Zooming in on kidney metabolism.
  23. Understanding lactate sensing and signalling.
  24. Metastatic triple negative breast cancer adapts its metabolism to destination tissues while retaining key metabolic signatures.
  25. Who knew? PPARs may act in the brain too.
  26. A regeneration-triggered metabolic adaptation is necessary for cell identity transitions and cell cycle re-entry to support blastema formation and bone regeneration.
  27. The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages.
  28. Analyzing cell-type-specific dynamics of metabolism in kidney repair.
  29. The F1Fo-ATPase inhibitor protein IF1 in pathophysiology.
  30. Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.
  31. Dietary Fructose and Fructose-Induced Pathologies.
  32. N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation.
  33. Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.
  34. Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals.
  35. KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress.
  36. Pervasive conditional selection of driver mutations and modular epistasis networks in cancer.
  37. The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells.
  38. SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer.
  39. KLF5 governs sphingolipid metabolism and barrier function of the skin.
  40. Pgc-1α controls epidermal stem cell fate and skin repair by sustaining NAD+ homeostasis during aging.
  41. Indole-3-acetic acid improves the hepatic mitochondrial respiration defects by PGC1a up-regulation.
  42. Leveraging lysine metabolism for renoprotection.
  1. Mol Cancer Res. 2022 Aug 22. pii: MCR-21-1032. [Epub ahead of print]
    Glutamine metabolism mediates sensitivity to respiratory complex II inhibition in acute myeloid leukemia.
    Alessia Roma, Matthew Tcheng, Nawaz Ahmed, Sarah Walker, Preethi Jayanth, Mark D Minden, Kristin Hope, Praveen P Nekkar Rao, Jessica Luc, Andrew C Doxey, Julie A Reisz, Rachel Culp-Hill, Angelo D'Alessandro, Paul A Spagnuolo.
      Acute myeloid leukemia (AML) is a hematological malignancy metabolically dependent on oxidative phosphorylation and mitochondrial electron transport chain (ETC) activity. AML cells are distinct from their normal hematopoietic counterparts by this metabolic reprogramming, which presents targets for new selective therapies. Here, metabolic changes in AML cells after ETC impairment are investigated. Genetic knockdown of the ETC complex II (CII) chaperone protein SDHAF1 (succinate dehydrogenase assembly factor 1) suppressed CII activity and delayed AML cell growth in vitro and in vivo. As a result, a novel small molecule that directly binds to the ubiquinone binding site of CII and inhibits its activity was identified. Pharmacological inhibition of CII induced selective cell death in AML cells while sparing normal hematopoietic progenitors. Through stable isotope tracing, results show that genetic or pharmacological inhibition of CII truncates the tricarboxylic acid cycle (TCA) and leads to anaplerotic glutamine metabolism to reestablish the truncated cycle. The inhibition of CII showed divergent fates of AML cells since they lacked the metabolic plasticity to adequately utilize glutamine metabolism, resulting in preferential depletion of key metabolites in the TCA cycle and death; normal cells were unaffected. These findings provide insight into the metabolic mechanisms that underlie AML's selective inhibition of CII. Implications: This work highlights the effects of direct CII inhibition in mediating selective AML cell death and provides insights into glutamine anaplerosis as a metabolic adaptation that can be therapeutically targeted.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-1032
  2. Nat Methods. 2022 Aug 25.
    Advances in measuring cancer cell metabolism with subcellular resolution.
    Victor Ruiz-Rodado, Adrian Lita, Mioara Larion.
      Characterizing metabolism in cancer is crucial for understanding tumor biology and for developing potential therapies. Although most metabolic investigations analyze averaged metabolite levels from all cell compartments, subcellular metabolomics can provide more detailed insight into the biochemical processes associated with the disease. Methodological limitations have historically prevented the wider application of subcellular metabolomics in cancer research. Recently, however, ways to distinguish and identify metabolic pathways within organelles have been developed, including state-of-the-art methods to monitor metabolism in situ (such as mass spectrometry-based imaging, Raman spectroscopy and fluorescence microscopy), to isolate key organelles via new approaches and to use tailored isotope-tracing strategies. Herein, we examine the advantages and limitations of these developments and look to the future of this field of research.
    DOI:  https://doi.org/10.1038/s41592-022-01572-6
  3. J Biol Chem. 2022 Aug 22. pii: S0021-9258(22)00853-5. [Epub ahead of print] 102410
    The histone deacetylases Rpd3 and Hst1 antagonistically regulate de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae.
    Benjamin Groth, Chi-Chun Huang, Su-Ju Lin.
      NAD+ is a cellular redox cofactor involved in many essential processes. The regulation of NAD+ metabolism and the signaling networks reciprocally interacting with NAD+-producing metabolic pathways are not yet fully understood. The NAD+-dependent histone deacetylase (HDAC) Hst1 has been shown to inhibit de novo NAD+ synthesis by repressing biosynthesis of nicotinic acid (BNA) gene expression. Here, we alternatively identify HDAC Rpd3 as a positive regulator of de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae. We reveal that deletion of RPD3 causes marked decreases in the production of de novo pathway metabolites, in direct contrast to deletion of HST1. We determined the BNA expression profiles of rpd3Δ and hst1Δ cells to be similarly opposed, suggesting the two HDACs may regulate the BNA genes in an antagonistic fashion. Our ChIP analysis revealed Rpd3 and Hst1 mutually influence each other's binding distribution at the BNA2 promoter. We demonstrate Hst1 to be the main deacetylase active at the BNA2 promoter, with hst1Δ cells displaying increased acetylation of the N-terminal tail lysine residues of histone H4, H4K5 and H4K12. Conversely, we show that deletion of RPD3 reduces the acetylation of these residues in a Hst1-dependent manner. This suggests Rpd3 may function to oppose spreading of Hst1-dependent heterochromatin and represents a unique form of antagonism between HDACs in regulating gene expression. Moreover, we found that Rpd3 and Hst1 also co-regulate additional targets involved in other branches of NAD+ metabolism. These findings help elucidate the complex interconnections involved in effecting the regulation of NAD+ metabolism.
    Keywords:  NAD(+) biosynthesis; cell metabolism; gene regulation; histone deacetylase; metabolic regulation; yeast genetics; yeast metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2022.102410
  4. Front Mol Biosci. 2022 ;9 930223
    Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
    Debora Gentile, Marianna Esposito, Paolo Grumati.
      Autophagy is an evolutionary conserved catabolic pathway that uses a unique double-membrane vesicle, called autophagosome, to sequester cytosolic components, deliver them to lysosomes and recycle amino-acids. Essentially, autophagy acts as a cellular cleaning system that maintains metabolic balance under basal conditions and helps to ensure nutrient viability under stress conditions. It is also an important quality control mechanism that removes misfolded or aggregated proteins and mediates the turnover of damaged and obsolete organelles. In this regard, the idea that autophagy is a non-selective bulk process is outdated. It is now widely accepted that forms of selective autophagy are responsible for metabolic rewiring in response to cellular demand. Given its importance, autophagy plays an essential role during tumorigenesis as it sustains malignant cellular growth by acting as a coping-mechanisms for intracellular and environmental stress that occurs during malignant transformation. Cancer development is accompanied by the formation of a peculiar tumor microenvironment that is mainly characterized by hypoxia (oxygen < 2%) and low nutrient availability. Such conditions challenge cancer cells that must adapt their metabolism to survive. Here we review the regulation of autophagy and selective autophagy by hypoxia and the crosstalk with other stress response mechanisms, such as UPR. Finally, we discuss the emerging role of ER-phagy in sustaining cellular remodeling and quality control during stress conditions that drive tumorigenesis.
    Keywords:  ER stress; ER-phagy; UPR; autophagy; cancer; endoplasmic reticulum; hypoxia
    DOI:  https://doi.org/10.3389/fmolb.2022.930223
  5. Cells. 2022 Aug 13. pii: 2518. [Epub ahead of print]11(16):
    An Epigenetic Role of Mitochondria in Cancer.
    Yu'e Liu, Chao Chen, Xinye Wang, Yihong Sun, Jin Zhang, Juxiang Chen, Yufeng Shi.
      Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
    Keywords:  cancer; epigenetics; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cells11162518
  6. Curr Biol. 2022 Aug 22. pii: S0960-9822(22)01126-5. [Epub ahead of print]32(16): R891-R894
    Cell death: All roads lead to mitochondria.
    Alexander Poltorak.
      Mitochondria are central to apoptosis, an immunologically silent form of cell death. The mitochondrial, or 'intrinsic', apoptotic pathway is activated when the permeabilized mitochondrial membrane of stressed cells releases apoptotic effectors. A new study now characterizes how mitochondria are involved in the switch from pyroptotic to necroptotic cell death.
    DOI:  https://doi.org/10.1016/j.cub.2022.07.025
  7. Biology (Basel). 2022 Jul 28. pii: 1132. [Epub ahead of print]11(8):
    Mitochondrial Ultrastructure and Activity Are Differentially Regulated by Glycolysis-, Krebs Cycle-, and Microbiota-Derived Metabolites in Monocytes.
    C Angélica Pérez-Hernández, M Maximina Bertha Moreno-Altamirano, Edgar O López-Villegas, Egle Butkeviciute, Mohammad Ali, Barbara Kronsteiner, Susanna J Dunachie, Hazel M Dockrell, Steven G Smith, F Javier Sánchez-García.
      Several intermediate metabolites harbour cell-signalling properties, thus, it is likely that specific metabolites enable the communication between neighbouring cells, as well as between host cells with the microbiota, pathogens, and tumour cells. Mitochondria, a source of intermediate metabolites, participate in a wide array of biological processes beyond that of ATP production, such as intracellular calcium homeostasis, cell signalling, apoptosis, regulation of immune responses, and host cell-microbiota crosstalk. In this regard, mitochondria's plasticity allows them to adapt their bioenergetics status to intra- and extra-cellular cues, and the mechanisms driving such plasticity are currently a matter of intensive research. Here, we addressed whether mitochondrial ultrastructure and activity are differentially shaped when human monocytes are exposed to an exogenous source of lactate (derived from glycolysis), succinate, and fumarate (Krebs cycle metabolic intermediates), or butyrate and acetate (short-chain fatty acids produced by intestinal microbiota). It has previously been shown that fumarate induces mitochondrial fusion, increases the mitochondrial membrane potential (Δψm), and reshapes the mitochondrial cristae ultrastructure. Here, we provide evidence that, in contrast to fumarate, lactate, succinate, and butyrate induce mitochondrial fission, while acetate induces mitochondrial swelling. These traits, along with mitochondrial calcium influx kinetics and glycolytic vs. mitochondrial ATP-production rates, suggest that these metabolites differentially shape mitochondrial function, paving the way for the understanding of metabolite-induced metabolic reprogramming of monocytes and its possible use for immune-response intervention.
    Keywords:  Krebs cycle; glycolysis; innate immunity; mitochondria; mitochondrial reprogramming; short-chain fatty acids
    DOI:  https://doi.org/10.3390/biology11081132
  8. Autophagy. 2022 Aug 26.
    EATING YOUR OWN FAT TO STAY FIT: LIPOPHAGY SUSTAINS LYMPHANGIOGENESIS.
    Odeta Mece, Diede Houbaert, Patrizia Agostinis.
      Lymphatic endothelial cells (LECs) exploit fatty acid oxidation (FAO) to grow and to maintain lymphatic vessel identity through the epigenetic regulation of the essential transcription factor PROX1. In our recent study, we found that LEC-specific loss of ATG5 prevents injury-induced lymphangiogenesis in vivo. Inadequate degradation of lipid droplets (LDs) caused by genetic ablation of ATG5 in LECs disturbs mitochondrial fitness, and reduces mitochondrial FAO and acetyl-CoA levels, ultimately affecting PROX1-mediated epigenetic regulation of CPT1A and key lymphatic markers, most importantly FLT4/VEGFR3. Supplementing the fatty acid precursor acetate rescues defective inflammation-driven lymphangiogenesis in LEC-specific atg5 knockout mice. Thus, efficient macroautophagy/autophagy-mediated LD breakdown is critical to maintain mitochondrial metabolism and acetyl-CoA levels, which sustain a PROX1-mediated lymphatic gene program required for LEC identity and inflammation-driven lymphangiogenesis.
    Keywords:  autophagy; lipid metabolism; lipophagy; lymphangiogenesis; lymphatic endothelial cells; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2022.2117513
  9. Cell Stem Cell. 2022 Aug 19. pii: S1934-5909(22)00304-6. [Epub ahead of print]
    Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.
    Xiaotong Hong, Joan Isern, Silvia Campanario, Eusebio Perdiguero, Ignacio Ramírez-Pardo, Jessica Segalés, Pablo Hernansanz-Agustín, Andrea Curtabbi, Oleg Deryagin, Angela Pollán, José A González-Reyes, José M Villalba, Marco Sandri, Antonio L Serrano, José A Enríquez, Pura Muñoz-Cánoves.
      Skeletal muscle regeneration depends on the correct expansion of resident quiescent stem cells (satellite cells), a process that becomes less efficient with aging. Here, we show that mitochondrial dynamics are essential for the successful regenerative capacity of satellite cells. The loss of mitochondrial fission in satellite cells-due to aging or genetic impairment-deregulates the mitochondrial electron transport chain (ETC), leading to inefficient oxidative phosphorylation (OXPHOS) metabolism and mitophagy and increased oxidative stress. This state results in muscle regenerative failure, which is caused by the reduced proliferation and functional loss of satellite cells. Regenerative functions can be restored in fission-impaired or aged satellite cells by the re-establishment of mitochondrial dynamics (by activating fission or preventing fusion), OXPHOS, or mitophagy. Thus, mitochondrial shape and physical networking controls stem cell regenerative functions by regulating metabolism and proteostasis. As mitochondrial fission occurs less frequently in the satellite cells in older humans, our findings have implications for regeneration therapies in sarcopenia.
    Keywords:  Drp1; OXPHOS; aging; metabolism; mitochondria; mitochondrial dynamics; mitophagy; muscle regeneration; muscle stem cells; satellite cells
    DOI:  https://doi.org/10.1016/j.stem.2022.07.009
  10. Redox Biol. 2022 Aug 13. pii: S2213-2317(22)00203-8. [Epub ahead of print]56 102431
    LIX1-mediated changes in mitochondrial metabolism control the fate of digestive mesenchyme-derived cells.
    Amandine Guérin, Claire Angebault, Sandrina Kinet, Chantal Cazevieille, Manuel Rojo, Jérémy Fauconnier, Alain Lacampagne, Arnaud Mourier, Naomi Taylor, Pascal de Santa Barbara, Sandrine Faure.
      YAP1 and TAZ are transcriptional co-activator proteins that play fundamental roles in many biological processes, from cell proliferation and cell lineage fate determination to tumorigenesis. We previously demonstrated that Limb Expression 1 (LIX1) regulates YAP1 and TAZ activity and controls digestive mesenchymal progenitor proliferation. However, LIX1 mode of action remains elusive. Here, we found that endogenous LIX1 is localized in mitochondria and is anchored to the outer mitochondrial membrane through S-palmitoylation of cysteine 84, a residue conserved in all LIX1 orthologs. LIX1 downregulation altered the mitochondrial ultrastructure, resulting in a significantly decreased respiration and attenuated production of mitochondrial reactive oxygen species (mtROS). Mechanistically, LIX1 knock-down impaired the stability of the mitochondrial proteins PHB2 and OPA1 that are found in complexes with mitochondrial-specific phospholipids and are required for cristae organization. Supplementation with unsaturated fatty acids counteracted the effects of LIX1 knock-down on mitochondrial morphology and ultrastructure and restored YAP1/TAZ signaling. Collectively, our data demonstrate that LIX1 is a key regulator of cristae organization, modulating mtROS level and subsequently regulating the signaling cascades that control fate commitment of digestive mesenchyme-derived cells.
    Keywords:  Cell fate; Cristae; Linoleic acid; Mitochondria; Sarcoma; Smooth muscle; YAP1/TAZ; mtROS
    DOI:  https://doi.org/10.1016/j.redox.2022.102431
  11. Cell Metab. 2022 Aug 15. pii: S1550-4131(22)00313-8. [Epub ahead of print]
    Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease.
    Larissa Traxler, Joseph R Herdy, Davide Stefanoni, Sophie Eichhorner, Silvia Pelucchi, Attila Szücs, Alice Santagostino, Yongsung Kim, Ravi K Agarwal, Johannes C M Schlachetzki, Christopher K Glass, Jessica Lagerwall, Douglas Galasko, Fred H Gage, Angelo D'Alessandro, Jerome Mertens.
      The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching of the glycolytic enzyme pyruvate kinase M (PKM) toward the cancer-associated PKM2 isoform conferred metabolic and transcriptional changes in AD iNs. These alterations occurred via PKM2's lack of metabolic activity and via nuclear translocation and association with STAT3 and HIF1α to promote neuronal fate loss and vulnerability. Chemical modulation of PKM2 prevented nuclear translocation, restored a mature neuronal metabolism, reversed AD-specific gene expression changes, and re-activated neuronal resilience against cell death.
    Keywords:  Alzheimer's disease; WGCNA; Warburg effect; cancer; direct conversion; induced neurons; metabolomics; pyruvate kinase M; reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.014
  12. Elife. 2022 Aug 23. pii: e79422. [Epub ahead of print]11
    β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveal their essential role as nutrient sensors for the KATP channel.
    Hannah R Foster, Thuong Ho, Evgeniy Potapenko, Sophia M Sdao, Shih Ming Huang, Sophie L Lewandowski, Halena R VanDeusen, Shawn M Davidson, Rebecca L Cardone, Marc Prentki, Richard G Kibbey, Matthew J Merrins.
      Pyruvate kinase (PK) and the phosphoenolpyruvate (PEP) cycle play key roles in nutrient-stimulated KATP channel closure and insulin secretion. To identify the PK isoforms involved, we generated mice lacking β-cell PKm1, PKm2, and mitochondrial PEP carboxykinase (PCK2) that generates mitochondrial PEP. Glucose metabolism generates both glycolytic and mitochondrially-derived PEP, which triggers KATP closure through local PKm1 and PKm2 signaling at the plasma membrane. Amino acids, which generate mitochondrial PEP without producing glycolytic fructose 1,6-bisphosphate to allosterically activate PKm2, signal through PKm1 to raise ATP/ADP, close KATP channels, and stimulate insulin secretion. Raising cytosolic ATP/ADP with amino acids is insufficient to close KATP channels in the absence of PK activity or PCK2, indicating that KATP channels are primarily regulated by PEP that provides ATP via plasma membrane-associated PK, rather than mitochondrially-derived ATP. Following membrane depolarization, the PEP cycle is also involved in an 'off-switch' that facilitates KATP channel reopening and Ca2+ extrusion, as shown by PK activation experiments and β-cell PCK2 deletion, which prolongs Ca2+ oscillations and increases insulin secretion. In conclusion, the differential response of PKm1 and PKm2 to the glycolytic and mitochondrial sources of PEP influences the β-cell nutrient response, and controls the oscillatory cycle regulating insulin secretion.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.79422
  13. J Pers Med. 2022 Aug 18. pii: 1329. [Epub ahead of print]12(8):
    MicroRNAs as Regulators of Cancer Cell Energy Metabolism.
    Natarajaseenivasan Suriya Muthukumaran, Prema Velusamy, Charles Solomon Akino Mercy, Dianne Langford, Kalimuthusamy Natarajaseenivasan, Santhanam Shanmughapriya.
      To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
    Keywords:  TCA; cancer metabolism; fatty acid oxidation; glucose oxidation; miRNA; pentose-phosphate pathway
    DOI:  https://doi.org/10.3390/jpm12081329
  14. Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2211310119
    NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity.
    Tom Meyer, Dor Shimon, Sawsan Youssef, Gal Yankovitz, Adi Tessler, Tom Chernobylsky, Anat Gaoni-Yogev, Rita Perelroizen, Noga Budick-Harmelin, Lawrence Steinman, Lior Mayo.
      Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are the most abundant glial cells in the CNS, and their dysfunction contributes to the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Recent advances highlight the pivotal role of cellular metabolism in programming immune responses. However, the underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive. Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme involved in cellular redox reactions and a substrate for NAD+-dependent enzymes. Cellular NAD+ levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with inflammation and disease. Here, we demonstrate that cell-autonomous generation of NAD+ via the salvage pathway regulates astrocyte immune function. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the salvage pathway, results in depletion of NAD+, inhibits oxidative phosphorylation, and limits astrocyte inflammatory potential. We identified CD38 as the main NADase up-regulated in reactive mouse and human astrocytes in models of neuroinflammation and MS. Genetic or pharmacological blockade of astrocyte CD38 activity augmented NAD+ levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential to inflammatory monocytes, and ameliorated EAE. We found that CD38 activity is mediated via calcineurin/NFAT signaling in mouse and human reactive astrocytes. Thus, NAMPT-NAD+-CD38 circuitry in astrocytes controls their ability to meet their energy demands and drives the expression of proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, MS. Our results identify candidate therapeutic targets in MS.
    Keywords:  Nicotinamide adenine dinucleotide; astrocyte; multiple sclerosis; neuroinflammation; tryptophan catabolism
    DOI:  https://doi.org/10.1073/pnas.2211310119
  15. J Neurosci. 2022 Aug 19. pii: JN-RM-0193-22. [Epub ahead of print]
    Glycerol-3-phosphate shuttle is a backup system securing metabolic flexibility in neurons.
    Ankit Dhoundiyal, Vanessa Goeschl, Stefan Boehm, Helmut Kubista, Matej Hotka.
      Electrical activity in neurons is highly energy demanding and accompanied by rises in cytosolic Ca2+ Cytosolic Ca2+, in turn, secures energy supply by pushing mitochondrial metabolism either through augmented NADH transfer into mitochondria via the malate aspartate shuttle (MAS) or via direct activation of dehydrogenases of the TCA cycle after passing into the matrix through the mitochondrial Ca2+ uniporter (MCU). Another Ca2+-sensitive booster of mitochondrial ATP synthesis is the glycerol-3-phosphate shuttle (G3PS) whose role in neuronal energy supply has remained elusive. Essential components of G3PS are expressed in hippocampal neurons. Single neuron metabolic measurements in primary hippocampal cultures derived from rat pups of either sex reveal only moderate, if any, constitutive activity of G3PS. However, during electrical activity neurons fully rely on G3PS when MAS and MCU are unavailable. Under these conditions, G3PS is required for appropriate action potential firing. Accordingly, G3PS safeguards metabolic flexibility of neurons to cope with energy demands of electrical signaling.SIGNIFICANCE STATEMENT:Ca2+ ions are known to provide a link between the energy-demanding electrical activity and an adequate ATP supply in neurons. To do so, Ca2+ acts both, from outside and inside of the mitochondrial inner membrane. Neuronal function critically depend on this regulation and its defects are often found in various neurological disorders. Although interest in neuronal metabolism increases, many aspects thereof have remained unresolved. In particular, a Ca2+-sensitive NADH shuttling system, the glycerol-3-phosphate shuttle, has been largely ignored with respect to its function in neurons. Our results demonstrate that this shuttle is functional in hippocampal neurons and safeguards ATP supply and appropriate action potential firing when malate aspartate shuttle and mitochondrial Ca2+ uniporter are unavailable, thereby ensuring neuronal metabolic flexibility.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0193-22.2022
  16. J Biol Chem. 2022 Aug 18. pii: S0021-9258(22)00844-4. [Epub ahead of print] 102401
    Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.
    Batuhan Yenilmez, Mark Kelly, Guofang Zhang, Nicole Wetoska, Olga R Ilkayeva, Kyounghee Min, Leslie Rowland, Chloe DiMarzio, Wentao He, Naideline Raymond, Lawrence Lifshitz, Meixia Pan, Xianlin Han, Jun Xie, Randall H Friedline, Jason K Kim, Guangping Gao, Mark A Herman, Christopher B Newgard, Michael P Czech.
      Hepatic steatosis associated with high fat diets (HFD), obesity and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl-coenzyme A (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high fat feeding is unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, while in contrast ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c (SREBP1c) and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels due to its increased conversion to Malonyl CoA (MalCoA) and palmitate. Together, these data indicate that in HFD-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or MalCoA, but rather by activities of DNL enzymes.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102401
  17. Antioxidants (Basel). 2022 Jul 29. pii: 1487. [Epub ahead of print]11(8):
    Reverse and Forward Electron Flow-Induced H2O2 Formation Is Decreased in α-Ketoglutarate Dehydrogenase (α-KGDH) Subunit (E2 or E3) Heterozygote Knock Out Animals.
    Gergő Horváth, Gergely Sváb, Tímea Komlódi, Dora Ravasz, Gergely Kacsó, Judit Doczi, Christos Chinopoulos, Attila Ambrus, László Tretter.
      α-ketoglutarate dehydrogenase complex (KGDHc), or 2-oxoglutarate dehydrogenase complex (OGDHc) is a rate-limiting enzyme in the tricarboxylic acid cycle, that has been identified in neurodegenerative diseases such as in Alzheimer's disease. The aim of the present study was to establish the role of the KGDHc and its subunits in the bioenergetics and reactive oxygen species (ROS) homeostasis of brain mitochondria. To study the bioenergetic profile of KGDHc, genetically modified mouse strains were used having a heterozygous knock out (KO) either in the dihydrolipoyl succinyltransferase (DLST+/-) or in the dihydrolipoyl dehydrogenase (DLD+/-) subunit. Mitochondrial oxygen consumption, hydrogen peroxide (H2O2) production, and expression of antioxidant enzymes were measured in isolated mouse brain mitochondria. Here, we demonstrate that the ADP-stimulated respiration of mitochondria was partially arrested in the transgenic animals when utilizing α-ketoglutarate (α-KG or 2-OG) as a fuel substrate. Succinate and α-glycerophosphate (α-GP), however, did not show this effect. The H2O2 production in mitochondria energized with α-KG was decreased after inhibiting the adenine nucleotide translocase and Complex I (CI) in the transgenic strains compared to the controls. Similarly, the reverse electron transfer (RET)-evoked H2O2 formation supported by succinate or α-GP were inhibited in mitochondria isolated from the transgenic animals. The decrease of RET-evoked ROS production by DLST+/- or DLD+/- KO-s puts the emphasis of the KGDHc in the pathomechanism of ischemia-reperfusion evoked oxidative stress. Supporting this notion, expression of the antioxidant enzyme glutathione peroxidase was also decreased in the KGDHc transgenic animals suggesting the attenuation of ROS-producing characteristics of KGDHc. These findings confirm the contribution of the KGDHc to the mitochondrial ROS production and in the pathomechanism of ischemia-reperfusion injury.
    Keywords:  DLD; DLST; KGDHc; OGDHc; RET; ROS; antioxidant systems; cellular respiration; ischemia-reperfusion; mitochondria; oxoglutarate dehydrogenase complex; reactive oxygen species; reverse electron transfer; succinate; transgenic animal; α-glycerophosphate; α-ketoglutarate dehydrogenase complex
    DOI:  https://doi.org/10.3390/antiox11081487
  18. Science. 2022 Aug 25. eabg6621
    Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.
    Hijai R Shin, Y Rose Citron, Lei Wang, Laura Tribouillard, Claire S Goul, Robin Stipp, Yusuke Sugasawa, Aakriti Jain, Nolwenn Samson, Chun-Yan Lim, Oliver B Davis, David Castaneda-Carpio, Mingxing Qian, Daniel K Nomura, Rushika M Perera, Eunyong Park, Douglas F Covey, Mathieu Laplante, Alex S Evers, Roberto Zoncu.
      Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified LYsosomal CHOlesterol Signaling (LYCHOS, previously annotated as G-protein coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1). Cholesterol bound to the N-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a GTPase-activating protein for the Rag guanosine triphosphatases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing, and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
    DOI:  https://doi.org/10.1126/science.abg6621
  19. Cells. 2022 Aug 20. pii: 2597. [Epub ahead of print]11(16):
    GPT2 Is Induced by Hypoxia-Inducible Factor (HIF)-2 and Promotes Glioblastoma Growth.
    Bo Zhang, Yan Chen, Lei Bao, Weibo Luo.
      Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene in human glioblastoma (GBM). Hypoxia upregulated GPT2 mRNA and protein levels in GBM cells, which required HIF-2 but not HIF-1. HIF-2 directly bound to the hypoxia response element of the human GPT2 gene, leading to its transcription in hypoxic GBM cells. GPT2 located at the nucleus and mitochondria and reduced α-ketoglutarate levels in GBM cells. Genetic or pharmacological inhibition of GPT2 decreased GBM cell growth and migration under normoxia and hypoxia. Knockout of GPT2 inhibited GBM tumor growth in mice. Collectively, these findings uncover a hypoxia-inducible aminotransferase GPT2 required for GBM progression.
    Keywords:  GPT2; glioblastoma; hypoxia; hypoxia-inducible factor; tumorigenesis
    DOI:  https://doi.org/10.3390/cells11162597
  20. NMR Biomed. 2022 Aug 23. e4817
    Recent Progress in Analysis of Intermediary Metabolism by ex vivo 13 C NMR.
    Craig R Malloy, A Dean Sherry, Jeffry R Alger, Eunsook S Jin.
      Advanced imaging technologies, large-scale metabolomics and the measurement of gene transcripts or enzyme expression all enable investigations of intermediary metabolism in human patients. Complementary information about fluxes in individual metabolic pathways may be obtained by ex vivo 13 C NMR of blood or tissue biopsies. Simple molecules such as 13 C-labeled glucose are readily administered to patients prior to surgical biopsies, and 13 C-labeled glycerol is easily administered orally to outpatients. Here we review recent progress in practical applications of 13 C NMR to study cancer biology, the response to oxidative stress, gluconeogenesis, triglyceride synthesis in patients, as well as new insights into compartmentation of metabolism in the cytosol. The technical aspects of obtaining the sample, preparing material for analysis, and acquiring the spectra are relatively simple. This approach enables convenient, valuable and quantitative insights into intermediary metabolism in patients.
    Keywords:  13C; NMR; cancer; glucose; glycerol; metabolic syndrome; stable isotope
    DOI:  https://doi.org/10.1002/nbm.4817
  21. Mol Metab. 2022 Aug 19. pii: S2212-8778(22)00146-6. [Epub ahead of print] 101577
    Peroxisomal regulation of energy homeostasis: Effect on obesity and related metabolic disorders.
    Brian Kleiboeker, Irfan J Lodhi.
      BACKGROUND: Peroxisomes are single membrane-bound organelles named for their role in hydrogen peroxide production and catabolism. However, their cellular functions extend well beyond reactive oxygen species (ROS) metabolism and include fatty acid oxidation of unique substrates that cannot be catabolized in mitochondria, and synthesis of ether lipids and bile acids. Metabolic functions of peroxisomes involve crosstalk with other organelles, including mitochondria, endoplasmic reticulum, lipid droplets and lysosomes. Emerging studies suggest that peroxisomes are important regulators of energy homeostasis and that disruption of peroxisomal functions influences the risk for obesity and the associated metabolic disorders, including type 2 diabetes and hepatic steatosis.SCOPE OF REVIEW: Here, we focus on the role of peroxisomes in ether lipid synthesis, β-oxidation and ROS metabolism, given that these functions have been most widely studied and have physiologically relevant implications in systemic metabolism and obesity. Efforts are made to mechanistically link these cellular and systemic processes.
    MAJOR CONCLUSIONS: Circulating plasmalogens, a form of ether lipids, have been identified as inversely correlated biomarkers of obesity. Ether lipids influence metabolic homeostasis through multiple mechanisms, including regulation of mitochondrial morphology and respiration affecting brown fat-mediated thermogenesis, and through regulation of adipose tissue development. Peroxisomal β-oxidation also affects metabolic homeostasis through generation of signaling molecules, such as acetyl-CoA and ROS that inhibit hydrolysis of stored lipids, contributing to development of hepatic steatosis. Oxidative stress resulting from increased peroxisomal β-oxidation-generated ROS in the context of obesity mediates β-cell lipotoxicity. A better understanding of the roles peroxisomes play in regulating and responding to obesity and its complications will provide new opportunities for their treatment.
    Keywords:  Diabetes; Fatty liver; Lipid metabolism; Obesity; Peroxisomes; Plasmalogen
    DOI:  https://doi.org/10.1016/j.molmet.2022.101577
  22. Nat Metab. 2022 Aug 25.
    Zooming in on kidney metabolism.
    Roland Nilsson.
      
    DOI:  https://doi.org/10.1038/s42255-022-00621-w
  23. Trends Endocrinol Metab. 2022 Aug 20. pii: S1043-2760(22)00136-9. [Epub ahead of print]
    Understanding lactate sensing and signalling.
    Michelangelo Certo, Alba Llibre, Wheeseong Lee, Claudio Mauro.
      Metabolites generated from cellular and tissue metabolism have been rediscovered in recent years as signalling molecules. They may act as cofactor of enzymes or be linked to proteins as post-translational modifiers. They also act as ligands for specific receptors, highlighting that their neglected functions have, in fact, a long standing in evolution. Lactate is one such metabolite that has been considered for long time a waste product of metabolism devoid of any biological function. However, in the past 10 years, lactate has gained much attention in several physio-pathological processes. Mechanisms of sensing and signalling have been discovered and implicated in a broad range of diseases, from cancer to inflammation and fibrosis, providing opportunities for novel therapeutic avenues. Here, we review some of the most recently discovered mechanisms of lactate sensing and signalling.
    Keywords:  G protein-coupled receptor; acidity; lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.tem.2022.07.004
  24. Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2205456119
    Metastatic triple negative breast cancer adapts its metabolism to destination tissues while retaining key metabolic signatures.
    Fariba Roshanzamir, Jonathan L Robinson, Daniel Cook, Mohammad Hossein Karimi-Jafari, Jens Nielsen.
      Triple negative breast cancer (TNBC) metastases are assumed to exhibit similar functions in different organs as in the original primary tumor. However, studies of metastasis are often limited to a comparison of metastatic tumors with primary tumors of their origin, and little is known about the adaptation to the local environment of the metastatic sites. We therefore used transcriptomic data and metabolic network analyses to investigate whether metastatic tumors adapt their metabolism to the metastatic site and found that metastatic tumors adopt a metabolic signature with some similarity to primary tumors of their destinations. The extent of adaptation, however, varies across different organs, and metastatic tumors retain metabolic signatures associated with TNBC. Our findings suggest that a combination of anti-metastatic approaches and metabolic inhibitors selected specifically for different metastatic sites, rather than solely targeting TNBC primary tumors, may constitute a more effective treatment approach.
    Keywords:  gene expression; genome-scale metabolic models; metastasis; systems biology; triple negative breast cancer
    DOI:  https://doi.org/10.1073/pnas.2205456119
  25. Nat Metab. 2022 Aug;4(8): 965-966
    Who knew? PPARs may act in the brain too.
    Randy J Seeley, Christopher J Rhodes.
      
    DOI:  https://doi.org/10.1038/s42255-022-00625-6
  26. Elife. 2022 Aug 22. pii: e76987. [Epub ahead of print]11
    A regeneration-triggered metabolic adaptation is necessary for cell identity transitions and cell cycle re-entry to support blastema formation and bone regeneration.
    Ana S Brandão, Jorge Borbinha, Telmo Pereira, Patrícia H Brito, Raquel Lourenço, Anabela Bensimon-Brito, Antonio Jacinto.
      Regeneration depends on the ability of mature cells at the injury site to respond to injury, generating tissue-specific progenitors that incorporate the blastema and proliferate to reconstitute the original organ architecture. The metabolic microenvironment has been tightly connected to cell function and identity during development and tumorigenesis. Yet, the link between metabolism and cell identity at the mechanistic level in a regenerative context remains unclear. The adult zebrafish caudal fin, and bone cells specifically, have been crucial for the understanding of mature cell contribution to tissue regeneration. Here, we use this model to explore the relevance of glucose metabolism for the cell fate transitions preceding new osteoblast formation and blastema assembly. We show that injury triggers a modulation in the metabolic profile at early stages of regeneration to enhance glycolysis at the expense of mitochondrial oxidation. This metabolic adaptation mediates transcriptional changes that make mature osteoblast amenable to be reprogramed into pre-osteoblasts and induces cell cycle re-entry and progression. Manipulation of the metabolic profile led to severe reduction of the pre-osteoblast pool, diminishing their capacity to generate new osteoblasts, and to a complete abrogation of blastema formation. Overall, our data indicate that metabolic alterations have a powerful instructive role in regulating genetic programs that dictate fate decisions and stimulate proliferation, thereby providing a deeper understanding on the mechanisms regulating blastema formation and bone regeneration.
    Keywords:  blastema; cell fate; cell metabolism; dedifferentiation; osteoblast; regeneration; regenerative medicine; stem cells; zebrafish
    DOI:  https://doi.org/10.7554/eLife.76987
  27. Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2121251119
    The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages.
    Phoenix Toboz, Mehdi Amiri, Negar Tabatabaei, Catherine R Dufour, Seung Hyeon Kim, Carine Fillebeen, Charles E Ayemoba, Arkady Khoutorsky, Manfred Nairz, Lijian Shao, Kostandin V Pajcini, Ki-Wook Kim, Vincent Giguère, Regiana L Oliveira, Marco Constante, Manuela M Santos, Carlos R Morales, Kostas Pantopoulos, Nahum Sonenberg, Sandra Pinho, Soroush Tahmasebi.
      GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that controls messenger RNA translation in response to amino acid availability and ribosome stalling. Here, we show that GCN2 controls erythrocyte clearance and iron recycling during stress. Our data highlight the importance of liver macrophages as the primary cell type mediating these effects. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2-/-) mice displayed resistance to anemia compared with wild-type (GCN2+/+) mice. GCN2-/- liver macrophages exhibited defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2-/- cells demonstrated that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating red blood cell clearance and iron recycling.
    Keywords:  GCN2; RBC; hemolytic stress; mRNA translation; macrophages
    DOI:  https://doi.org/10.1073/pnas.2121251119
  28. Nat Metab. 2022 Aug 25.
    Analyzing cell-type-specific dynamics of metabolism in kidney repair.
    Gangqi Wang, Bram Heijs, Sarantos Kostidis, Ahmed Mahfouz, Rosalie G J Rietjens, Roel Bijkerk, Angela Koudijs, Loïs A K van der Pluijm, Cathelijne W van den Berg, Sébastien J Dumas, Peter Carmeliet, Martin Giera, Bernard M van den Berg, Ton J Rabelink.
      A common drawback of metabolic analyses of complex biological samples is the inability to consider cell-to-cell heterogeneity in the context of an organ or tissue. To overcome this limitation, we present an advanced high-spatial-resolution metabolomics approach using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) combined with isotope tracing. This method allows mapping of cell-type-specific dynamic changes in central carbon metabolism in the context of a complex heterogeneous tissue architecture, such as the kidney. Combined with multiplexed immunofluorescence staining, this method can detect metabolic changes and nutrient partitioning in targeted cell types, as demonstrated in a bilateral renal ischemia-reperfusion injury (bIRI) experimental model. Our approach enables us to identify region-specific metabolic perturbations associated with the lesion and throughout recovery, including unexpected metabolic anomalies in cells with an apparently normal phenotype in the recovery phase. These findings may be relevant to an understanding of the homeostatic capacity of the kidney microenvironment. In sum, this method allows us to achieve resolution at the single-cell level in situ and hence to interpret cell-type-specific metabolic dynamics in the context of structure and metabolism of neighboring cells.
    DOI:  https://doi.org/10.1038/s42255-022-00615-8
  29. Front Physiol. 2022 ;13 917203
    The F1Fo-ATPase inhibitor protein IF1 in pathophysiology.
    Cristina Gatto, Martina Grandi, Giancarlo Solaini, Alessandra Baracca, Valentina Giorgio.
      The endogenous inhibitor of ATP synthase is a protein of about 10 kDa, known as IF1 which binds to the catalytic domain of the enzyme during ATP hydrolysis. The main role of IF1 consists of limiting ATP dissipation under condition of severe oxygen deprivation or in the presence of dysfunctions of mitochondrial respiratory complexes, causing a collapse in mitochondrial membrane potential and therefore ATP hydrolysis. New roles of IF1 are emerging in the fields of cancer and neurodegeneration. Its high expression levels in tumor tissues have been associated with different roles favouring tumor formation, progression and evasion. Since discordant mechanisms of action have been proposed for IF1 in tumors, it is of the utmost importance to clarify them in the prospective of defining novel approaches for cancer therapy. Other IF1 functions, including its involvement in mitophagy, may be protective for neurodegenerative and aging-related diseases. In the present review we aim to clarify and discuss the emerging mechanisms in which IF1 is involved, providing a critical view of the discordant findings in the literature.
    Keywords:  ATP synthase; cancer; inhibitor protein IF1; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3389/fphys.2022.917203
  30. Hum Mol Genet. 2022 Aug 22. pii: ddac201. [Epub ahead of print]
    Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.
    Paola Zanfardino, Giovanna Longo, Alessandro Amati, Federica Morani, Ernesto Picardi, Francesco Girolamo, Mariella Pafundi, Sharon N Cox, Caterina Manzari, Apollonia Tullo, Stefano Doccini, Filippo M Santorelli, Vittoria Petruzzella.
      Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on the mitochondrial altered phenotypes in patient-derived fibroblasts harboring MFN2 mutations and in animal models have been reported. We addressed some of these issues by focusing on mitochondria behavior during autophagy and mitophagy in fibroblasts derived from a CMT2AMFN2 patient with an MFN2650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity, and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. We found that MFN2 mutated fibroblasts showed impairment of mitochondrial morphology, bioenergetics capacity, and impairment of the early stages of autophagy, but not mitophagy. Unexpectedly, transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. We consistently found the activation of mTORC2/AKT signaling and accelerated proliferation in the CMT2AMFN2 fibroblasts. In conclusion, our evidence indicates that MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.
    DOI:  https://doi.org/10.1093/hmg/ddac201
  31. Annu Rev Nutr. 2022 Aug 22. 42 45-66
    Dietary Fructose and Fructose-Induced Pathologies.
    Sunhee Jung, Hosung Bae, Won-Suk Song, Cholsoon Jang.
      The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases.
    Keywords:  fatty liver; fructose; gut microbiota; intestine; ketohexokinase; lipogenesis
    DOI:  https://doi.org/10.1146/annurev-nutr-062220-025831
  32. Nat Metab. 2022 Aug;4(8): 1041-1054
    N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation.
    Hao Peng, Binbin Chen, Wei Wei, Siyao Guo, Hui Han, Chunlong Yang, Jieyi Ma, Lu Wang, Sui Peng, Ming Kuang, Shuibin Lin.
      Aberrant RNA modifications lead to dysregulated gene expression and cancer progression. Ribosomal RNA (rRNA) accounts for more than 80% of a cell's total RNA, but the functions and molecular mechanisms underlying rRNA modifications in cancers are poorly understood. Here, we show that the 18S rRNA N6-methyladenosine (m6A) methyltransferase complex METTL5-TRMT112 is upregulated in various cancer types and correlated with poor prognosis. In addition, we demonstrate the critical functions of METTL5 in promoting hepatocellular carcinoma (HCC) tumorigenesis in vitro and in mouse models. Mechanistically, depletion of METTL5-mediated 18S rRNA m6A modification results in impaired 80S ribosome assembly and decreased translation of mRNAs involved in fatty acid metabolism. We further reveal that ACSL4 mediates the function of METTL5 on fatty acid metabolism and HCC progression, and targeting ACSL4 and METTL5 synergistically inhibits HCC tumorigenesis in vivo. Our study uncovers mechanistic insights underlying mRNA translation control and HCC tumorigenesis through lipid metabolism remodeling and provides a molecular basis for the development of therapeutic strategies for HCC treatment.
    DOI:  https://doi.org/10.1038/s42255-022-00622-9
  33. Nat Commun. 2022 Aug 22. 13(1): 4918
    Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.
    Ying Xue Xie, Nima N Naseri, Jasmine Fels, Parinati Kharel, Yoonmi Na, Diane Lane, Jacqueline Burré, Manu Sharma.
      Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson's disease, the molecular-cellular mechanism(s) remain unclear. To study this, we generated a new mouse model to specifically immunoisolate neuronal lysosomes, and established a long-term culture model where αSyn aggregates are produced within neurons without the addition of exogenous fibrils. We show that neuronally generated pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis. The released aggregates are non-membrane enveloped and seeding-competent. Additionally, we find that this release is dependent on neuronal activity and cytosolic Ca2+. These results propose lysosomal exocytosis as a central mechanism for the release of aggregated and degradation-resistant proteins from neurons.
    DOI:  https://doi.org/10.1038/s41467-022-32625-1
  34. Nat Commun. 2022 Aug 23. 13(1): 4652
    Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals.
    Yasuko O Abe, Hikari Yoshitane, Dae Wook Kim, Satoshi Kawakami, Michinori Koebis, Kazuki Nakao, Atsu Aiba, Jae Kyoung Kim, Yoshitaka Fukada.
      In mammals, the circadian clock consists of transcriptional and translational feedback loops through DNA cis-elements such as E-box and RRE. The E-box-mediated core feedback loop is interlocked with the RRE-mediated feedback loop, but biological significance of the RRE-mediated loop has been elusive. In this study, we established mutant cells and mice deficient for rhythmic transcription of Bmal1 gene by deleting its upstream RRE elements and hence disrupted the RRE-mediated feedback loop. We observed apparently normal circadian rhythms in the mutant cells and mice, but a combination of mathematical modeling and experiments revealed that the circadian period and amplitude of the mutants were more susceptible to disturbance of CRY1 protein rhythm. Our findings demonstrate that the RRE-mediated feedback regulation of Bmal1 underpins the E-box-mediated rhythm in cooperation with CRY1-dependent posttranslational regulation of BMAL1 protein, thereby conferring the perturbation-resistant oscillation and chronologically-organized output of the circadian clock.
    DOI:  https://doi.org/10.1038/s41467-022-32326-9
  35. Nat Commun. 2022 Aug 23. 13(1): 4941
    KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress.
    Jan-Renier Moonen, James Chappell, Minyi Shi, Tsutomu Shinohara, Dan Li, Maxwell R Mumbach, Fan Zhang, Ramesh V Nair, Joseph Nasser, Daniel H Mai, Shalina Taylor, Lingli Wang, Ross J Metzger, Howard Y Chang, Jesse M Engreitz, Michael P Snyder, Marlene Rabinovitch.
      Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote this beneficial response. We show that under LSS, KLF4 interacts with the SWI/SNF nucleosome remodeling complex to increase accessibility at enhancer sites that promote the expression of homeostatic endothelial genes. By combining molecular and computational approaches we discover enhancers that loop to promoters of KLF4- and LSS-responsive genes that stabilize endothelial cells and suppress inflammation, such as BMPR2, SMAD5, and DUSP5. By linking enhancers to genes that they regulate under physiologic LSS, our work establishes a foundation for interpreting how non-coding DNA variants in these regions might disrupt protective gene expression to influence vascular disease.
    DOI:  https://doi.org/10.1038/s41467-022-32566-9
  36. Cell Rep. 2022 Aug 23. pii: S2211-1247(22)01092-0. [Epub ahead of print]40(8): 111272
    Pervasive conditional selection of driver mutations and modular epistasis networks in cancer.
    Jaime Iranzo, George Gruenhagen, Jorge Calle-Espinosa, Eugene V Koonin.
      Cancer driver mutations often display mutual exclusion or co-occurrence, underscoring the key role of epistasis in carcinogenesis. However, estimating the magnitude of epistasis and quantifying its effect on tumor evolution remains a challenge. We develop a method (Coselens) to quantify conditional selection on the excess of nonsynonymous substitutions in cancer genes. Coselens infers the number of drivers per gene in different partitions of a cancer genomics dataset using covariance-based mutation models and determines whether coding mutations in a gene affect selection for drivers in any other gene. Using Coselens, we identify 296 conditionally selected gene pairs across 16 cancer types in the TCGA dataset. Conditional selection affects 25%-50% of driver substitutions in tumors with >2 drivers. Conditionally co-selected genes form modular networks, whose structures challenge the traditional interpretation of within-pathway mutual exclusivity and across-pathway synergy, suggesting a more complex scenario where gene-specific across-pathway epistasis shapes differentiated cancer subtypes.
    Keywords:  CP: Cancer; cancer genomics; cancer subtypes; co-occurrence; conditional selection; driver mutation; epistasis; mutational landscape; mutual exclusivity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111272
  37. Cell Stem Cell. 2022 Aug 19. pii: S1934-5909(22)00333-2. [Epub ahead of print]
    The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells.
    Nicole Baker, Steven Wade, Matthew Triolo, John Girgis, Damian Chwastek, Sarah Larrigan, Peter Feige, Ryo Fujita, Colin Crist, Michael A Rudnicki, Yan Burelle, Mireille Khacho.
      Quiescence regulation is essential for adult stem cell maintenance and sustained regeneration. Our studies uncovered that physiological changes in mitochondrial shape regulate the quiescent state of adult muscle stem cells (MuSCs). We show that MuSC mitochondria rapidly fragment upon an activation stimulus, via systemic HGF/mTOR, to drive the exit from deep quiescence. Deletion of the mitochondrial fusion protein OPA1 and mitochondrial fragmentation transitions MuSCs into G-alert quiescence, causing premature activation and depletion upon a stimulus. OPA1 loss activates a glutathione (GSH)-redox signaling pathway promoting cell-cycle progression, myogenic gene expression, and commitment. MuSCs with chronic OPA1 loss, leading to mitochondrial dysfunction, continue to reside in G-alert but acquire severe cell-cycle defects. Additionally, we provide evidence that OPA1 decline and impaired mitochondrial dynamics contribute to age-related MuSC dysfunction. These findings reveal a fundamental role for OPA1 and mitochondrial dynamics in establishing the quiescent state and activation potential of adult stem cells.
    Keywords:  G-alert; GSH; OPA1; ROS; adult muscle stem cells; aging; glutathione; mTOR; mitochondrial dynamics; quiescence; reactive oxygen species; stem cell activation; stem cell maintenance; systemic factors
    DOI:  https://doi.org/10.1016/j.stem.2022.07.010
  38. Cell Rep. 2022 Aug 23. pii: S2211-1247(22)01084-1. [Epub ahead of print]40(8): 111266
    SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer.
    Patrik Simmler, Cédric Cortijo, Lisa Maria Koch, Patricia Galliker, Silvia Angori, Hella Anna Bolck, Christina Mueller, Ana Vukolic, Peter Mirtschink, Yann Christinat, Natalie R Davidson, Kjong-Van Lehmann, Giovanni Pellegrini, Chantal Pauli, Daniela Lenggenhager, Ilaria Guccini, Till Ringel, Christian Hirt, Kim Fabiano Marquart, Moritz Schaefer, Gunnar Rätsch, Matthias Peter, Holger Moch, Markus Stoffel, Gerald Schwank.
      Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demonstrate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1α, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mechanism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 impedes tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer. Our work uncovers an essential role of SF3B1 in HIF1 signaling, thereby providing a potential explanation for the link between high SF3B1 expression and aggressiveness of solid tumors.
    Keywords:  CP: Cancer; HIF1 transcription; SF3B1; chromophobe renal cell carcinoma; glycolysis; hypoxia; pancreatic cancer; splicing
    DOI:  https://doi.org/10.1016/j.celrep.2022.111266
  39. Genes Dev. 2022 Aug 25.
    KLF5 governs sphingolipid metabolism and barrier function of the skin.
    Ying Lyu, Yinglu Guan, Lisa Deliu, Ericka Humphrey, Joanna K Frontera, Youn Joo Yang, Daniel Zamler, Kun Hee Kim, Vakul Mohanty, Kevin Jin, Vakul Mohanty, Virginia Liu, Jinzhuang Dou, Lucas J Veillon, Shwetha V Kumar, Philip L Lorenzi, Yang Chen, Kathleen M McAndrews, Sergei Grivennikov, Xingzhi Song, Jianhua Zhang, Yuanxin Xi, Jing Wang, Ken Chen, Priyadharsini Nagarajan, Yejing Ge.
      Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found that KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we established KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage-defining factor across tissue types.
    Keywords:  barrier; secretory; skin epidermis; sphingolipid metabolism; stem cells; transcription factors
    DOI:  https://doi.org/10.1101/gad.349662.122
  40. Mol Metab. 2022 Aug 17. pii: S2212-8778(22)00144-2. [Epub ahead of print] 101575
    Pgc-1α controls epidermal stem cell fate and skin repair by sustaining NAD+ homeostasis during aging.
    Wesley Wong, Elizabeth D Crane, Hui Zhang, Jiahe Li, Tovah A Day, Alex E Green, Keir J Menzies, Justin D Crane.
      OBJECTIVE: The epidermal barrier is renewed by the activation, proliferation, and differentiation of keratinocyte stem cells after injury and aging impedes this repair process through undefined mechanisms. We previously identified a gene signature of metabolic dysfunction in aged murine epidermis, but the precise regulators of epidermal repair and age-related growth defects are not well established. Aged mouse models as well as mice with conditional epidermal loss of the metabolic regulator, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1α) were used to explore the cellular pathways which control skin repair after injury and stress.METHODS: Aged mice or those with epidermal Pgc-1α deletion (epiPgc-1α KO) and young or Pgc1afl/fl controls were subjected to wound injury, UVB exposure or the inflammatory agent TPA. In vivo and ex vivo analyses of wound closure, skin structure, cell growth and stem cell differentiation were used to understand changes in epidermal re-growth and repair resulting from aging or Pgc-1α loss.
    RESULTS: Aging impairs epidermal re-growth during wound healing and results in lower expression of Pgc-1α. Mice with conditional deletion of epidermal Pgc-1α exhibit greater inflammation- and UVB-induced cell differentiation, reduced proliferation, and slower wound healing. epiPgc-1α KO mice also displayed reduced keratinocyte NAD+ levels, shorter telomeres, and greater poly ADP-ribosylation, resulting in enhanced stress-stimulated p53 and p21 signaling. When NAD+ was reduced by Pgc-1α loss or pharmacologic inhibition of NAD+ synthesis, there was reduced stress-induced proliferation, increased differentiation, and protection against DNA damage via enhanced epidermal shedding. Similarly, aged mice exhibit disrupted epidermal NAD+ homeostasis and enhanced p53 activation, resulting in p21 growth arrest after wounding. NAD+ precursor treatment restores epidermal growth from old skin to that of young.
    CONCLUSIONS: Our studies identify a novel role for epidermal Pgc-1α in controlling epidermal repair via its regulation of cellular NAD+ and downstream effects on p53-driven growth arrest. We also establish that parallel mechanisms are evident in aged epidermis, showing that NAD+ signaling is an important controller of physiologic skin repair and that dysfunction of this pathway contributes to age-related wound repair defects.
    Keywords:  Aging; NAD(+); epidermis; wound healing
    DOI:  https://doi.org/10.1016/j.molmet.2022.101575
  41. Cell Signal. 2022 Aug 18. pii: S0898-6568(22)00204-2. [Epub ahead of print] 110442
    Indole-3-acetic acid improves the hepatic mitochondrial respiration defects by PGC1a up-regulation.
    Chen Zhang, Qingsong Fu, Kai Shao, Limin Liu, Xiaotian Ma, Fengyi Zhang, Xiaodong Zhang, Liying Meng, ChuanZhu Yan, Xiaoyun Zhao.
      Recent evidences have linked indole-3-acetic acid (I3A), a gut microbiota-derived metabolite from dietary tryptophan, with the protection against non-alcoholic fatty liver disease (NAFLD). However, the values of I3A on mitochondrial homeostasis in NAFLD have yet to be analyzed. In this study, we verified that I3A alleviated dietary-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis. Importantly, we expanded the understanding of I3A further to enhance mitochondrial oxidative phosphorylation in the liver by RNA-seq. Consistently, I3A restored the deficiency of mitochondrial respiration complex (MRC) capacity in palmitic acid (PA)-induced HepG2 without initiating oxidative stress in vitro. These changes were dependent on peroxisome proliferator-activated receptor γ coactivator 1 (PGC1)-a, a key regulator of mitochondrial biogenesis. Silencing of PGC1a by siRNA and pharmacologic inhibitor SR-18292, blocked the restoration of I3A on mitochondrial oxidative phosphorylation. In addition, pre-treatment of I3A guarded against the deficiency of MRC capacity. In conclusion, our findings uncovered that I3A increased hepatic PGC1a expression, contributing to mitochondrial respiration improvement in NAFLD.
    Keywords:  Indole-3-acetic acid; Mitochondria; Non-alcoholic fatty liver disease; Oxidative phosphorylation; Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110442
  42. Nat Rev Nephrol. 2022 Aug 26.
    Leveraging lysine metabolism for renoprotection.
    Monica Wang.
      
    DOI:  https://doi.org/10.1038/s41581-022-00625-5
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