bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022–01–30
forty papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity.
  2. Dual role of Mic10 in mitochondrial cristae organization and ATP synthase-linked metabolic adaptation and respiratory growth.
  3. Circadian control of mitochondria in ROS homeostasis.
  4. The mitochondrial LYR protein, SDHAF1 is required for succinate dehydrogenase activity in Arabidopsis.
  5. Seventh BHD international symposium: recent scientific and clinical advancement.
  6. Mitochondria and Viral Infection: Advances and Emerging Battlefronts.
  7. Metabolic regulation of ferroptosis in the tumor microenvironment.
  8. BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16.
  9. The mixed blessing of AMPK signaling in Cancer treatments.
  10. Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.
  11. The Development of Single-Cell Metabolism and Its Role in Studying Cancer Emergent Properties.
  12. Sodium in mitochondrial redox signaling.
  13. Compartmentalization of telomeres through DNA-scaffolded phase separation.
  14. Metabolic signatures of regulation by phosphorylation and acetylation.
  15. Mitochondria modulate ameloblast Ca2+ signaling.
  16. Measurement of Protein Import Capacity of Skeletal Muscle Mitochondria.
  17. Mitochondria, energy, and metabolism in neuronal health and disease.
  18. Reductive stress triggers ANAC017-mediated retrograde signaling to safeguard the endoplasmic reticulum by boosting mitochondrial respiratory capacity.
  19. scDART-seq reveals distinct m6A signatures and mRNA methylation heterogeneity in single cells.
  20. Rethinking the bioavailability and cellular transport properties of S-adenosylmethionine.
  21. Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome.
  22. Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer.
  23. Mitochondrial DNA variation across 56,434 individuals in gnomAD.
  24. Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition.
  25. Understanding metabolic alterations and heterogeneity in cancer progression through validated immunodetection of key molecular components: a case of carbonic anhydrase IX.
  26. p53 in ferroptosis regulation: the new weapon for the old guardian.
  27. Lipid droplet-mitochondria coupling via Perilipin 5 augments respiratory capacity but is dispensable for FA oxidation.
  28. A subset of synaptic transmission events is coupled to acetyl coenzyme A production.
  29. Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer.
  30. The long noncoding RNA glycoLINC assembles a lower glycolytic metabolon to promote glycolysis.
  31. Eukaryotic lipid droplets: metabolic hubs, and immune first responders.
  32. Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis.
  33. Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource.
  34. Macrophage calcium reporter mice reveal immune cell communication in vitro and in vivo.
  35. Intersection of autophagy regulation and circadian rhythms in the heart.
  36. Macrophages activated by hepatitis B virus have distinct metabolic profiles and suppress the virus via IL-1β to downregulate PPARα and FOXO3.
  37. Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development.
  38. Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription.
  39. Medium branched chain fatty acids improve the profile of tricarboxylic acid cycle intermediates in mitochondrial fatty acid β-oxidation deficient cells: A comparative study.
  40. Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.
  1. Life Sci Alliance. 2022 Apr;pii: e202101157. [Epub ahead of print]5(4):
    Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity.
    Amy Tarangelo, Jason Rodencal, Joon Tae Kim, Leslie Magtanong, Jonathan Z Long, Scott J Dixon.
      Nucleotide synthesis is a metabolically demanding process essential for DNA replication and other processes in the cell. Several anticancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2 RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR results in conservation of intracellular glutathione, limiting the accumulation of toxic lipid peroxides and preventing the onset of ferroptosis in response to cystine deprivation. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.
    DOI:  https://doi.org/10.26508/lsa.202101157
  2. Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01805-2. [Epub ahead of print]38(4): 110290
    Dual role of Mic10 in mitochondrial cristae organization and ATP synthase-linked metabolic adaptation and respiratory growth.
    Heike Rampelt, Florian Wollweber, Mariya Licheva, Rinse de Boer, Inge Perschil, Liesa Steidle, Thomas Becker, Maria Bohnert, Ida van der Klei, Claudine Kraft, Martin van der Laan, Nikolaus Pfanner.
      Invaginations of the mitochondrial inner membrane, termed cristae, are hubs for oxidative phosphorylation. The mitochondrial contact site and cristae organizing system (MICOS) and the dimeric F1Fo-ATP synthase play important roles in controlling cristae architecture. A fraction of the MICOS core subunit Mic10 is found in association with the ATP synthase, yet it is unknown whether this interaction is of relevance for mitochondrial or cellular functions. Here, we established conditions to selectively study the role of Mic10 at the ATP synthase. Mic10 variants impaired in MICOS functions stimulate ATP synthase oligomerization like wild-type Mic10 and promote efficient inner membrane energization, adaptation to non-fermentable carbon sources, and respiratory growth. Mic10's functions in respiratory growth largely depend on Mic10ATPsynthase, not on Mic10MICOS. We conclude that Mic10 plays a dual role as core subunit of MICOS and as partner of the F1Fo-ATP synthase, serving distinct functions in cristae shaping and respiratory adaptation and growth.
    Keywords:  ATP synthase; MICOS; Mic10; cristae organization; inner membrane; membrane architecture; membrane potential; metabolic adaptation; mitochondria; respiration
    DOI:  https://doi.org/10.1016/j.celrep.2021.110290
  3. Antioxid Redox Signal. 2022 Jan 24.
    Circadian control of mitochondria in ROS homeostasis.
    Volha Mezhnina, Oghogho P Ebeigbe, Allan Poe, Roman V Kondratov.
       SIGNIFICANCE: Mitochondria produce most of the cellular ATP through the process of oxidative phosphorylation. Energy metabolism in the mitochondria is associated with the production of reactive oxygen species (ROS). Excessive ROS production leads to oxidative stress and compromises cellular physiology. Energy metabolism in the mitochondria depends on nutrient flux and cellular metabolic needs, which are in turn connected with the feeding/fasting cycle. In animals, the feeding/fasting cycle is controlled by the circadian clock that generates 24-hour rhythms in behavior, metabolism and signaling. Recent Advances. Here, we discuss the role of the circadian clock and rhythms in mitochondria on ROS homeostasis. Circadian clock is involved in mitochondrial ROS production and detoxification through control of nutrient flux and oxidation, uncoupling, antioxidant defense and mitochondrial dynamics.
    CRITICAL ISSUES: Little is known on molecular mechanisms of circadian control of mitochondria functions. The circadian clock regulates the expression and activity of mitochondrial metabolic and antioxidant enzymes. The regulation involves a direct transcriptional control by CLOCK/BMAL1, NRF2 transcriptional network and sirtuin dependent posttranslational protein modifications. Future Perspectives. We hypothesize that the circadian clock orchestrates mitochondria physiology to synchronize it with the feeding/fasting cycle. Circadian coordination of mitochondrial function couples energy metabolism with diets and contributes to antioxidant defense to prevent metabolic diseases and delay aging.
    DOI:  https://doi.org/10.1089/ars.2021.0274
  4. Plant J. 2022 Jan 26.
    The mitochondrial LYR protein, SDHAF1 is required for succinate dehydrogenase activity in Arabidopsis.
    Ying Li, Katharina Belt, Saad F Alqahtani, Saurabh Saha, Ricarda Fenske, Olivier Van Aken, James Whelan, A Harvey Millar, Monika W Murcha, Shaobai Huang.
      Succinate dehydrogenase (SDH, complex II), which plays an essential role in mitochondrial respiratory and tricarboxylic acid metabolism requires the assembly of eight nuclear encoded subunits and the insertion of various cofactors. Here, we report on the characterisation of an Arabidopsis thaliana Leucine-Tyrosine-Arginine (LYR) protein family member (SDHAF1, At2g39725) as a factor required for SDH activity. SDHAF1 is located in mitochondria and can fully complement the yeast SDHAF1 deletion strain. Knockdown of SDHAF1 using RNA interference (RNAi) resulted in a decrease in seedling hypocotyl elongation and reduced SDH activity. Proteomic analyses revealed a decreased abundance of various SDH subunits and assembly factors. Protein interaction assays revealed that SDHAF1 can interact exclusively with the Fe-S cluster containing subunit SDH2 and HSCB, a co-chaperone involved in Fe-S cluster complex recruitment. Therefore, we propose that in Arabidopsis, SDHAF1 plays a role in the biogenesis of SDH2 to form the functional complex II essential for mitochondrial respiration and metabolism.
    Keywords:  Iron-sulfur cluster insertion; Mitochondrial metabolism; assembly factors; complex II; succinate dehydrogenase
    DOI:  https://doi.org/10.1111/tpj.15684
  5. Oncotarget. 2022 ;13 173-181
    Seventh BHD international symposium: recent scientific and clinical advancement.
    Mark R Woodford, Avgi Andreou, Masaya Baba, Irma van de Beek, Chiara Di Malta, Iris Glykofridis, Hannah Grimes, Elizabeth P Henske, Othon Iliopoulos, Masatoshi Kurihara, Romain Lazor, W Marston Linehan, Kenki Matsumoto, Stefan J Marciniak, Yukiko Namba, Arnim Pause, Neil Rajan, Anindita Ray, Laura S Schmidt, Wei Shi, Ortrud K Steinlein, Julia Thierauf, Roberto Zoncu, Anna Webb, Mehdi Mollapour.
      The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients' experiences living with this malady.
    Keywords:  Birt-Hogg-Dubé syndrome; FLCN; LDHA; folliculin; tuberous sclerosis complex
    DOI:  https://doi.org/10.18632/oncotarget.28176
  6. mBio. 2022 Jan 25. e0209621
    Mitochondria and Viral Infection: Advances and Emerging Battlefronts.
    Mahsa Sorouri, Tyron Chang, Dustin C Hancks.
      Mitochondria are dynamic organelles vital for energy production with now appreciated roles in immune defense. During microbial infection, mitochondria serve as signaling hubs to induce immune responses to counteract invading pathogens like viruses. Mitochondrial functions are central to a variety of antiviral responses including apoptosis and type I interferon signaling (IFN-I). While apoptosis and IFN-I mediated by mitochondrial antiviral signaling (MAVS) are well-established defenses, new dimensions of mitochondrial biology are emerging as battlefronts during viral infection. Increasingly, it has become apparent that mitochondria serve as reservoirs for distinct cues that trigger immune responses and that alterations in mitochondrial morphology may also tip infection outcomes. Furthermore, new data are foreshadowing pivotal roles for classic, homeostatic facets of this organelle as host-virus interfaces, namely, the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) complexes like respiratory supercomplexes. Underscoring the importance of "housekeeping" mitochondrial activities in viral infection is the growing list of viral-encoded inhibitors including mimics derived from cellular genes that antagonize these functions. For example, virologs for ETC factors and several enzymes from the TCA cycle have been recently identified in DNA virus genomes and serve to pinpoint new vulnerabilities during infection. Here, we highlight recent advances for known antiviral functions associated with mitochondria as well as where the next battlegrounds may be based on viral effectors. Collectively, new methodology and mechanistic insights over the coming years will strengthen our understanding of how an ancient molecular truce continues to defend cells against viruses.
    Keywords:  C15orf48; DAMP; MAVS; MISTR; NDUFA4; OXPHOS; TCA cycle; apoptosis; interferon; micropeptides; mimics; mitochondria; mitochondrial dynamics; mtDNA; mtROS; mtdsRNA; pyroptosis; supercomplexes; virologs; virus
    DOI:  https://doi.org/10.1128/mbio.02096-21
  7. J Biol Chem. 2022 Jan 20. pii: S0021-9258(22)00057-6. [Epub ahead of print] 101617
    Metabolic regulation of ferroptosis in the tumor microenvironment.
    Nneka E Mbah, Costas A Lyssiotis.
      Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death triggered by impaired redox and antioxidant machinery and propagated by the accumulation of toxic lipid peroxides. A compendium of experimental studies suggest that ferroptosis is tumor-suppressive. Sensitivity or resistance to ferroptosis can be regulated by cell-autonomous and non-cell-autonomous metabolic mechanisms. This includes a role for ferroptosis that extends beyond the tumor cells themselves, mediated by components of the tumor microenvironment, including T cells and other immune cells. Herein, we review the intrinsic and extrinsic factors that promote the sensitivity of cancer cells to ferroptosis and conclude by describing approaches to harness the full utility of ferroptotic agents as therapeutic options for cancer therapy.
    Keywords:  cancer; ferroptosis; metabolism; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2022.101617
  8. Nat Metab. 2022 Jan 24.
    BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16.
    Qi-Xiang Ma, Wen-Ying Zhu, Xiao-Chen Lu, Duo Jiang, Feng Xu, Jin-Tao Li, Lei Zhang, Ying-Li Wu, Zheng-Jun Chen, Miao Yin, Hai-Yan Huang, Qun-Ying Lei.
      The link between branched-chain amino acids (BCAAs) and obesity has been known for decades but the functional role of BCAA metabolism in white adipose tissue (WAT) of obese individuals remains vague. Here, we show that mice with adipose tissue knockout of Bcat2, which converts BCAAs to branched-chain keto acids (BCKAs), are resistant to high-fat diet-induced obesity due to increased inguinal WAT browning and thermogenesis. Mechanistically, acetyl-CoA derived from BCKA suppresses WAT browning by acetylation of PR domain-containing protein 16 (PRDM16) at K915, disrupting the interaction between PRDM16 and peroxisome proliferator-activated receptor-γ (PPARγ) to maintain WAT characteristics. Depletion of BCKA-derived acetyl-CoA robustly prompts WAT browning and energy expenditure. In contrast, BCKA supplementation re-establishes high-fat diet-induced obesity in Bcat2 knockout mice. Moreover, telmisartan, an anti-hypertension drug, significantly represses Bcat2 activity via direct binding, resulting in enhanced WAT browning and reduced adiposity. Strikingly, BCKA supplementation reverses the lean phenotype conferred by telmisartan. Thus, we uncover the critical role of the BCAA-BCKA axis in WAT browning.
    DOI:  https://doi.org/10.1038/s42255-021-00520-6
  9. BMC Cancer. 2022 Jan 25. 22(1): 105
    The mixed blessing of AMPK signaling in Cancer treatments.
    Mehrshad Sadria, Deokhwa Seo, Anita T Layton.
       BACKGROUND: Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state.
    METHODS: To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary differential equation-based mechanistic model of AMPK-mTORC signaling, and parametrized the model based on existing experimental data.
    RESULTS: Model simulations were conducted to yield the following predictions: (i) increasing AMPK activity has opposite effects on mTORC depending on the nutrient availability; (ii) indirect inhibition of AMPK activity through inhibition of sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low nutrient availability; (iii) the balance between cell proliferation and survival exhibits an intricate dependence on DEP domain-containing mTOR-interacting protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition of mTORC2 and activation of AMPK is a potential strategy for suppressing both cell survival and proliferation.
    CONCLUSIONS: Taken together, model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.
    Keywords:  AMPK; Cancer; Dynamical system; Metabolism; mTORC
    DOI:  https://doi.org/10.1186/s12885-022-09211-1
  10. Dev Cell. 2022 Jan 24. pii: S1534-5807(21)01040-6. [Epub ahead of print]57(2): 260-276.e9
    Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.
    Rani Ojha, Ishaq Tantray, Suman Rimal, Siddhartha Mitra, Sam Cheshier, Bingwei Lu.
      Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.
    Keywords:  NAD(+)/NADH; Sirtuin; Warburg effect; glioblastoma multiforme; inflammation; metabolic reprogramming; mitochondrial complex I; non-canonical Notch signaling; reactive oxygen species; reverse electron transport
    DOI:  https://doi.org/10.1016/j.devcel.2021.12.020
  11. Front Oncol. 2021 ;11 814085
    The Development of Single-Cell Metabolism and Its Role in Studying Cancer Emergent Properties.
    Dingju Wei, Meng Xu, Zhihua Wang, Jingjing Tong.
      Metabolic reprogramming is one of the hallmarks of malignant tumors, which provides energy and material basis for tumor rapid proliferation, immune escape, as well as extensive invasion and metastasis. Blocking the energy and material supply of tumor cells is one of the strategies to treat tumor, however tumor cell metabolic heterogeneity prevents metabolic-based anti-cancer treatment. Therefore, searching for the key metabolic factors that regulate cell cancerous change and tumor recurrence has become a major challenge. Emerging technology--single-cell metabolomics is different from the traditional metabolomics that obtains average information of a group of cells. Single-cell metabolomics identifies the metabolites of single cells in different states by mass spectrometry, and captures the molecular biological information of the energy and substances synthesized in single cells, which provides more detailed information for tumor treatment metabolic target screening. This review will combine the current research status of tumor cell metabolism with the advantages of single-cell metabolomics technology, and explore the role of single-cell sequencing technology in searching key factors regulating tumor metabolism. The addition of single-cell technology will accelerate the development of metabolism-based anti-cancer strategies, which may greatly improve the prognostic survival rate of cancer patients.
    Keywords:  cancer metabolism; metabolic heterogeneity; metabolic reprogramming; single-cell metabolomics; tumor drug resistance
    DOI:  https://doi.org/10.3389/fonc.2021.814085
  12. Antioxid Redox Signal. 2022 Jan 24.
    Sodium in mitochondrial redox signaling.
    Pablo Hernansanz-Agustín, José Antonio Enríquez.
       BACKGROUND: Mitochondrial Na+ has been discovered as a new second messenger regulating inner mitochondrial membrane (IMM) fluidity and ROS production by complex III (CIII). However, the roles of mitochondrial Na+ in mitochondrial redox signalling go beyond than initially expected.
    SIGNIFICANCE: In this review, we systematize the current knowledge on mitochondrial Na+ homeostasis and its implications on different modes of ROS production by mitochondria. Na+ behaves as a positive modulator of forward mitochondrial ROS production by either complex III (CIII) or by decreasing antioxidant capacity of mitochondria, and as a potential negative modulator of reverse electron transfer (RET) by complex I (CI). Such duality depends on the bioenergetic status, cation and redox contexts, and can either lead to potential adaptations or cell death.
    FUTURE DIRECTIONS: Direct Na+ interaction with phospholipids, proven in the IMM, allows us to hypothesize its potential role in the existence and function of lipid rafts in other biological membranes regarding redox homeostasis, as well as the potential role of other monovalent cations in membrane biology. Thus, we provide the reader an update on the emerging field of mitochondrial Na+ homeostasis and its relationship with mitochondrial redox signalling.
    DOI:  https://doi.org/10.1089/ars.2021.0262
  13. Dev Cell. 2022 Jan 24. pii: S1534-5807(21)01037-6. [Epub ahead of print]57(2): 277-290.e9
    Compartmentalization of telomeres through DNA-scaffolded phase separation.
    Amanda Jack, Yoonji Kim, Amy R Strom, Daniel S W Lee, Byron Williams, Jeffrey M Schaub, Elizabeth H Kellogg, Ilya J Finkelstein, Luke S Ferro, Ahmet Yildiz, Clifford P Brangwynne.
      Telomeres form unique nuclear compartments that prevent degradation and fusion of chromosome ends by recruiting shelterin proteins and regulating access of DNA damage repair factors. To understand how these dynamic components protect chromosome ends, we combine in vivo biophysical interrogation and in vitro reconstitution of human shelterin. We show that shelterin components form multicomponent liquid condensates with selective biomolecular partitioning on telomeric DNA. Tethering and anomalous diffusion prevent multiple telomeres from coalescing into a single condensate in mammalian cells. However, telomeres coalesce when brought into contact via an optogenetic approach. TRF1 and TRF2 subunits of shelterin drive phase separation, and their N-terminal domains specify interactions with telomeric DNA in vitro. Telomeric condensates selectively recruit telomere-associated factors and regulate access of DNA damage repair factors. We propose that shelterin mediates phase separation of telomeric chromatin, which underlies the dynamic yet persistent nature of the end-protection mechanism.
    Keywords:  DNA repair; chromatin organization; phase separation; shelterin; telomeres
    DOI:  https://doi.org/10.1016/j.devcel.2021.12.017
  14. iScience. 2022 Jan 21. 25(1): 103730
    Metabolic signatures of regulation by phosphorylation and acetylation.
    Kirk Smith, Fangzhou Shen, Ho Joon Lee, Sriram Chandrasekaran.
      Acetylation and phosphorylation are highly conserved posttranslational modifications (PTMs) that regulate cellular metabolism, yet how metabolic control is shared between these PTMs is unknown. Here we analyze transcriptome, proteome, acetylome, and phosphoproteome datasets in E. coli, S. cerevisiae, and mammalian cells across diverse conditions using CAROM, a new approach that uses genome-scale metabolic networks and machine learning to classify targets of PTMs. We built a single machine learning model that predicted targets of each PTM in a condition across all three organisms based on reaction attributes (AUC>0.8). Our model predicted phosphorylated enzymes during a mammalian cell-cycle, which we validate using phosphoproteomics. Interpreting the machine learning model using game theory uncovered enzyme properties including network connectivity, essentiality, and condition-specific factors such as maximum flux that differentiate targets of phosphorylation from acetylation. The conserved and predictable partitioning of metabolic regulation identified here between these PTMs may enable rational rewiring of regulatory circuits.
    Keywords:  Metabolic flux analysis; Omics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103730
  15. FASEB J. 2022 Feb;36(2): e22169
    Mitochondria modulate ameloblast Ca2+ signaling.
    Veronica Costiniti, Guilherme H S Bomfim, Maria Neginskaya, Ga-Yeon Son, Erna Mitaishvili, Marta Giacomello, Evgeny Pavlov, Rodrigo S Lacruz.
      The role of mitochondria in enamel, the most mineralized tissue in the body, is poorly defined. Enamel is formed by ameloblast cells in two main sequential stages known as secretory and maturation. Defining the physiological features of each stage is essential to understand mineralization. Here, we analyzed functional features of mitochondria in rat primary secretory and maturation-stage ameloblasts focusing on their role in Ca2+ signaling. Quantification of the Ca2+ stored in the mitochondria by trifluoromethoxy carbonylcyanide phenylhydrazone stimulation was comparable in both stages. The release of endoplasmic reticulum Ca2+ pools by adenosine triphosphate in rhod2AM-loaded cells showed similar mitochondrial Ca2+ (m Ca2+ ) uptake. However, m Ca2+ extrusion via Na+ -Li+ -Ca2+ exchanger was more prominent in maturation. To address if m Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) played a role in cytosolic Ca2+ (c Ca2+ ) buffering, we stimulated Ca2+ influx via the store-operated Ca2+ entry (SOCE) and blocked MCU with the inhibitor Ru265. This inhibitor was first tested using the enamel cell line LS8 cells. Ru265 prevented c Ca2+ clearance in permeabilized LS8 cells like ruthenium red, and it did not affect ΔΨm in intact cells. In primary ameloblasts, SOCE stimulation elicited a significantly higher m Ca2+ uptake in maturation ameloblasts. The uptake of Ca2+ into the mitochondria was dramatically decreased in the presence of Ru265. Combined, these results suggest an increased mitochondrial Ca2+ handling in maturation but only upon stimulation of Ca2+ influx via SOCE. These functional studies provide insights not only on the role of mitochondria in ameloblast Ca2+ physiology, but also advance the concept that SOCE and m Ca2+ uptake are complementary processes in biological mineralization.
    Keywords:  MCU; enamel; maturation; mitochondria; secretory
    DOI:  https://doi.org/10.1096/fj.202100602R
  16. J Vis Exp. 2022 Jan 07.
    Measurement of Protein Import Capacity of Skeletal Muscle Mitochondria.
    Ashley N Oliveira, Brandon J Richards, David A Hood.
      Mitochondria are key metabolic and regulatory organelles that determine the energy supply as well as the overall health of the cell. In skeletal muscle, mitochondria exist in a series of complex morphologies, ranging from small oval organelles to a broad, reticulum-like network. Understanding how the mitochondrial reticulum expands and develops in response to diverse stimuli such as alterations in energy demand has long been a topic of research. A key aspect of this growth, or biogenesis, is the import of precursor proteins, originally encoded by the nuclear genome, synthesized in the cytosol, and translocated into various mitochondrial sub-compartments. Mitochondria have developed a sophisticated mechanism for this import process, involving many selective inner and outer membrane channels, known as the protein import machinery (PIM). Import into the mitochondrion is dependent on viable membrane potential and the availability of organelle-derived ATP through oxidative phosphorylation. Therefore its measurement can serve as a measure of organelle health. The PIM also exhibits a high level of adaptive plasticity in skeletal muscle that is tightly coupled to the energy status of the cell. For example, exercise training has been shown to increase import capacity, while muscle disuse reduces it, coincident with changes in markers of mitochondrial content. Although protein import is a critical step in the biogenesis and expansion of mitochondria, the process is not widely studied in skeletal muscle. Thus, this paper outlines how to use isolated and fully functional mitochondria from skeletal muscle to measure protein import capacity in order to promote a greater understanding of the methods involved and an appreciation of the importance of the pathway for organelle turnover in exercise, health, and disease.
    DOI:  https://doi.org/10.3791/63055
  17. FEBS Lett. 2022 Jan 28.
    Mitochondria, energy, and metabolism in neuronal health and disease.
    Diogo Trigo, Catarina Avelar, Miguel Fernandes, Juliana Sá, Odete da Cruz E Silva.
      Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles in ensuring that varying energetic demands are rapidly met to maintain neuronal and axonal energy homeostasis. Recent evidence associates ageing and neurodegeneration with anomalous neuronal metabolism, as age-dependent alterations of neuronal metabolism are now believed to occur prior to neurodegeneration. The brain has a high energy demand, which makes it particularly sensitive to mitochondrial dysfunction. Distinct cellular events causing oxidative stress or disruption of metabolism and mitochondrial homeostasis can trigger a neuropathology. This review explores the bioenergetic hypothesis for the neurodegenerative pathomechanisms, discussing factors leading to age-related brain hypometabolism and its contribution to cognitive decline. Recent research on the mitochondrial network in healthy nervous system cells, its response to stress and how it is affected by pathology, as well as current contributions to novel therapeutic approaches will be highlighted.
    Keywords:  Alzheimer; Huntington; Parkinson; ROS; ageing; axon; mitochondria; mitophagy; neurodegeneration; neuron
    DOI:  https://doi.org/10.1002/1873-3468.14298
  18. Plant Cell. 2022 Jan 25. pii: koac017. [Epub ahead of print]
    Reductive stress triggers ANAC017-mediated retrograde signaling to safeguard the endoplasmic reticulum by boosting mitochondrial respiratory capacity.
    Philippe Fuchs, Finja Bohle, Sophie Lichtenauer, José Manuel Ugalde, Elias Feitosa Araujo, Berivan Mansuroglu, Cristina Ruberti, Stephan Wagner, Stefanie J Müller-Schüssele, Andreas J Meyer, Markus Schwarzländer.
      Redox processes are at the heart of universal life processes, such as metabolism, signaling or folding of secreted proteins. Redox landscapes differ between cell compartments and are strictly controlled to tolerate changing conditions and to avoid cell dysfunction. While a sophisticated antioxidant network counteracts oxidative stress, our understanding of reductive stress responses remains fragmentary. Here, we observed root growth impairment in Arabidopsis thaliana mutants of mitochondrial alternative oxidase 1a (aox1a) in response to the model thiol reductant dithiothreitol (DTT). Mutants of mitochondrial uncoupling protein 1 (ucp1) displayed a similar phenotype indicating that impaired respiratory flexibility led to hypersensitivity. Endoplasmic reticulum (ER) stress was enhanced in the mitochondrial mutants and limiting endoplasmic reticulum oxidoreductin (ERO) capacity in the aox1a background led to synergistic root growth impairment by DTT, indicating that mitochondrial respiration alleviates reductive ER stress. The observations that DTT triggered NAD reduction in vivo and that the presence of thiols led to electron transport chain activity in isolated mitochondria offer a biochemical framework of mitochondrion-mediated alleviation of thiol-mediated reductive stress. Ablation of transcription factor ANAC017 impaired the induction of AOX1a expression by DTT and led to DTT hypersensitivity, revealing that reductive stress tolerance is achieved by adjusting mitochondrial respiratory capacity via retrograde signaling. Our data reveal an unexpected role for mitochondrial respiratory flexibility and retrograde signaling in reductive stress tolerance involving inter-organelle redox crosstalk.
    DOI:  https://doi.org/10.1093/plcell/koac017
  19. Mol Cell. 2022 Jan 17. pii: S1097-2765(21)01143-6. [Epub ahead of print]
    scDART-seq reveals distinct m6A signatures and mRNA methylation heterogeneity in single cells.
    Matthew Tegowski, Mathieu N Flamand, Kate D Meyer.
      N6-methyladenosine (m6A) is an abundant RNA modification that plays critical roles in RNA regulation and cellular function. Global m6A profiling has revealed important aspects of m6A distribution and function, but to date such studies have been restricted to large populations of cells. Here, we develop a method to identify m6A sites transcriptome-wide in single cells. We uncover surprising heterogeneity in the presence and abundance of m6A sites across individual cells and identify differentially methylated mRNAs across the cell cycle. Additionally, we show that cellular subpopulations can be distinguished based on their RNA methylation signatures, independent from gene expression. These studies reveal fundamental features of m6A that have been missed by m6A profiling of bulk cells and suggest the presence of cell-intrinsic mechanisms for m6A deposition.
    DOI:  https://doi.org/10.1016/j.molcel.2021.12.038
  20. Cell Stress. 2022 Jan;6(1): 1-5
    Rethinking the bioavailability and cellular transport properties of S-adenosylmethionine.
    Yudong Sun, Jason W Locasale.
      S-adenosylmethionine (SAM) is a versatile metabolite that participates in a wide range of reactions such as methylation and transsulfuration. These capabilities allow SAM to influence cellular processes such as gene expression and redox balancing. The importance of SAM is highlighted by its widespread usage as an over-the-counter nutrient supplement and as an experimental reagent in molecular biology. The bioavailability and cellular transport properties of SAM, however, are often overlooked under these contexts, putting limits on SAM's therapeutic potential and complicating the interpretation of experimental results. In this article, we examined the chemical stability and cellular permeability of SAM, proposed a schematic for indirect SAM transport across the mammalian plasma membrane, and lastly discussed the implications arising from such transport schematic.
    Keywords:  S-adenosyl-methionine; SAM; metabolism; methionine
    DOI:  https://doi.org/10.15698/cst2022.01.261
  21. J Neurol. 2022 Jan 28.
    Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome.
    María Paz Guerrero-Molina, Montserrat Morales-Conejo, Aitor Delmiro, María Morán, Cristina Domínguez-González, Elena Arranz-Canales, Ana Ramos-González, Joaquín Arenas, Miguel A Martín, Jesús González de la Aleja.
       BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients.
    METHODS: This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined.
    RESULTS: Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 μmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 μmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS.
    CONCLUSIONS: Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.
    Keywords:  Branched-chain amino acids; Glutamate; Glutamine; MELAS; Mitochondrial disease
    DOI:  https://doi.org/10.1007/s00415-021-10942-7
  22. Nat Commun. 2022 Jan 24. 13(1): 466
    Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer.
    Nikita Sushentsev, Mary A McLean, Anne Y Warren, Arnold J V Benjamin, Cara Brodie, Amy Frary, Andrew B Gill, Julia Jones, Joshua D Kaggie, Benjamin W Lamb, Matthew J Locke, Jodi L Miller, Ian G Mills, Andrew N Priest, Fraser J L Robb, Nimish Shah, Rolf S Schulte, Martin J Graves, Vincent J Gnanapragasam, Kevin M Brindle, Tristan Barrett, Ferdia A Gallagher.
      Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.
    DOI:  https://doi.org/10.1038/s41467-022-28069-2
  23. Genome Res. 2022 Jan 24. pii: gr.276013.121. [Epub ahead of print]
    Mitochondrial DNA variation across 56,434 individuals in gnomAD.
    Genome Aggregation Database Consortium
      Genomic databases of allele frequency are extremely helpful for evaluating clinical variants of unknown significance; however, until now, databases such as the Genome Aggregation Database (gnomAD) have focused on nuclear DNA and have ignored the mitochondrial genome (mtDNA). Here we present a pipeline to call mtDNA variants that addresses three technical challenges: (i) detecting homoplasmic and heteroplasmic variants, present respectively in all or a fraction of mtDNA molecules, (ii) circular mtDNA genome, and (iii) misalignment of nuclear sequences of mitochondrial origin (NUMTs). We observed that mtDNA copy number per cell varied across gnomAD cohorts and influenced the fraction of NUMT-derived false-positive variant calls, which can account for the majority of putative heteroplasmies. To avoid false positives, we excluded contaminated samples, cell lines, and samples prone to NUMT misalignment due to few mtDNA copies. Furthermore, we report variants with heteroplasmy greater than 10%. We applied this pipeline to 56,434 whole genome sequences in the gnomAD v3.1 database that includes individuals of European (58%), African (25%), Latino (10%), and Asian (5%) ancestry. Our gnomAD v3.1 release contains population frequencies for 10,850 unique mtDNA variants at more than half of all mtDNA bases. We report frequencies within each nuclear ancestral population and mitochondrial haplogroup. Homoplasmic variants account for most variant calls (98%) and unique variants (85%). We observed that 1/250 individuals carry a pathogenic mtDNA variant with heteroplasmy above 10%. These mtDNA population allele frequencies are freely accessible and will aid in diagnostic interpretation and research studies.
    DOI:  https://doi.org/10.1101/gr.276013.121
  24. Front Cell Dev Biol. 2021 ;9 738916
    Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition.
    Buse Cevatemre, Engin Ulukaya, Egemen Dere, Sukru Dilege, Ceyda Acilan.
      Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.
    Keywords:  cancer metabolism; drug resistance; epithelial mesenchymal transition; lung cancer; pyruvate dehydrogenase complex
    DOI:  https://doi.org/10.3389/fcell.2021.738916
  25. Cancer Metastasis Rev. 2022 Jan 26.
    Understanding metabolic alterations and heterogeneity in cancer progression through validated immunodetection of key molecular components: a case of carbonic anhydrase IX.
    Martina Takacova, Ivana Kajanova, Maria Kolarcikova, Jana Lapinova, Miriam Zatovicova, Silvia Pastorekova.
      Cancer metabolic heterogeneity develops in response to both intrinsic factors (mutations leading to activation of oncogenic pathways) and extrinsic factors (physiological and molecular signals from the extracellular milieu). Here we review causes and consequences of metabolic alterations in cancer cells with focus on hypoxia and acidosis, and with particular attention to carbonic anhydrase IX (CA IX). CA IX is a cancer-associated enzyme induced and activated by hypoxia in a broad range of tumor types, where it participates in pH regulation as well as in molecular mechanisms supporting cancer cells' invasion and metastasis. CA IX catalyzes reversible conversion of carbon dioxide to bicarbonate ion plus proton and cooperates with a spectrum of molecules transporting ions or metabolites across the plasma membrane. Thereby CA IX contributes to extracellular acidosis as well as to buffering intracellular pH, which is essential for cell survival, metabolic performance, and proliferation of cancer cells. Since CA IX expression pattern reflects gradients of oxygen, pH, and other intratumoral factors, we use it as a paradigm to discuss an impact of antibody quality and research material on investigating metabolic reprogramming of tumor tissue. Based on the validation, we propose the most reliable CA IX-specific antibodies and suggest conditions for faithful immunohistochemical analysis of molecules contributing to heterogeneity in cancer progression.
    Keywords:  Acidosis; Antibody validation; Carbonic anhydrase IX; Heterogeneity; Hypoxia; Metabolism
    DOI:  https://doi.org/10.1007/s10555-021-10011-5
  26. Cell Death Differ. 2022 Jan 27.
    p53 in ferroptosis regulation: the new weapon for the old guardian.
    Yanqing Liu, Wei Gu.
      Although the conventional activities of p53 such as cell cycle arrest, senescence, and apoptosis are well accepted as the major checkpoints in stress responses, accumulating evidence implicates the importance of other tumor suppression mechanisms. Among these unconventional activities, an iron-dependent form of non-apoptotic cell death, termed ferroptosis, attracts great interest. Unlike apoptotic cell death, activation of p53 alone is not sufficient to induce ferroptosis directly; instead, through its metabolic targets, p53 is able to modulate the ferroptosis response in the presence of ferroptosis inducers such as GPX4 inhibitors or high levels of ROS. Here, we review the role of ferroptosis in p53-mediated tumor suppression, with a focus on what cellular factors are critical for p53-dependent ferroptosis during tumor suppression and how p53 modulates both the canonical (GPX4-dependent) and the non-canonical (GPX4-independent) ferroptosis pathways. We also discuss the possibility of targeting p53-mediated ferroptotic responses for the treatment of human cancers and potentially, other diseases.
    DOI:  https://doi.org/10.1038/s41418-022-00943-y
  27. J Lipid Res. 2022 Jan 20. pii: S0022-2275(22)00005-0. [Epub ahead of print] 100172
    Lipid droplet-mitochondria coupling via Perilipin 5 augments respiratory capacity but is dispensable for FA oxidation.
    Benedikt Kien, Stephanie Kolleritsch, Natalia Kunowska, Christoph Heier, Gabriel Chalhoub, Anna Tilp, Heimo Wolinski, Ulrich Stelzl, Guenter Haemmerle.
      Disturbances in lipid homeostasis can cause mitochondrial dysfunction and lipotoxicity. Perilipin 5 (PLIN5) decorates intracellular lipid droplets (LD) in oxidative tissues and controls triacylglycerol (TG) turnover via its interactions with Adipose triglyceride lipase (ATGL) and the ATGL co-activator Comparative gene identification-58 (CGI-58). Furthermore, PLIN5 anchors mitochondria to the LD membrane via the outermost part of the carboxyl-terminus. However, the role of this LD-mitochondria coupling (LDMC) in cellular energy catabolism is less established. In this study, we investigated the impact of PLIN5-mediated LDMC in comparison to disrupted LDMC on cellular TG homeostasis, FA oxidation, mitochondrial respiration and protein interaction. To do so, we established PLIN5 mutants deficient in LDMC whilst maintaining normal interactions with key lipolytic players. Radiotracer studies with cell lines stably overexpressing wild type or truncated PLIN5 revealed that LDMC has no significant impact on FA esterification upon lipid loading or TG catabolism during stimulated lipolysis. Moreover, we demonstrated that LDMC exerts a minor if any role in mitochondrial FA oxidation. In contrast, LDMC significantly improved the mitochondrial respiratory capacity and metabolic flexibility of lipid-challenged cardiomyocytes, which was corroborated by LDMC-dependent interactions of PLIN5 with mitochondrial proteins involved in mitochondrial respiration, dynamics and cristae organization. Taken together, this study suggests that PLIN5 preserves mitochondrial function by adjusting FA supply via the regulation of TG hydrolysis and that LDMC is a vital part of mitochondrial integrity.
    Keywords:  Adipose-triglyceride lipase; Comparative gene identification-58; Lipid droplets; PLIN5; cardiovascular disease; fatty acid oxidation; lipid droplet-mitochondria coupling; lipolysis; lipotoxicity; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.jlr.2022.100172
  28. J Neurophysiol. 2022 Jan 26.
    A subset of synaptic transmission events is coupled to acetyl coenzyme A production.
    Vikram Jakkamsetti, Qian Ma, Juan M Pascual.
      Biological principles sustain the inference that synaptic function is coupled to neural metabolism, but the precise relationship between these two activities is not known. For example, it is unclear whether all synaptic transmission events are uniformly dependent on metabolic flux. Most synapses utilize glutamate and the principal metabolic function of the brain is glucose oxidation, which starts with glycolysis. Thus, we asked how glutamatergic synaptic currents are modified by partial deficiency of the main glycolytic enzyme pyruvate dehydrogenase (PDH), which generates the intermediary metabolism product acetyl coenzyme A (acetyl-CoA). Using brain slices obtained from mice genetically modified to harbor a behaviorally relevant degree of PDH suppression, we also asked whether such impact is indeed metabolic via the bypassing of PDH with a glycolysis-independent acetyl-CoA substrate. We analyzed spontaneous synaptic currents under recording that minimize artificial metabolic augmentation. Principal component analysis identified synaptic charge transfer as the major difference between a subset of wild type and PDH-deficient (PDHD) postsynaptic currents. This was due to reduced charge transfer as well as diminished current rise and decay times. The alternate acetyl-CoA source acetate rapidly restored these features but only for events of large amplitude as revealed by correlational and kernel density analyses. Application of tetrodotoxin to block large-amplitude events evoked by action potentials removed synaptic event charge transfer and decay-time differences between wild type and PDHD neurons. These results suggest that glucose metabolic flux and excitatory transmission are intimately coupled for synaptic events characterized by large current amplitude.
    Keywords:  Inhibitory; Metabolism; Synapse
    DOI:  https://doi.org/10.1152/jn.00200.2021
  29. Proc Natl Acad Sci U S A. 2022 Feb 01. pii: e2117754119. [Epub ahead of print]119(5):
    Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer.
    Stella V Paffenholz, Camilla Salvagno, Yu-Jui Ho, Matthew Limjoco, Timour Baslan, Sha Tian, Amanda Kulick, Elisa de Stanchina, John E Wilkinson, Francisco M Barriga, Dmitriy Zamarin, Juan R Cubillos-Ruiz, Josef Leibold, Scott W Lowe.
      High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.
    Keywords:  cancer immunotherapy; mouse models; ovarian cancer; senescence
    DOI:  https://doi.org/10.1073/pnas.2117754119
  30. Mol Cell. 2022 Jan 22. pii: S1097-2765(21)00997-7. [Epub ahead of print]
    The long noncoding RNA glycoLINC assembles a lower glycolytic metabolon to promote glycolysis.
    Youming Zhu, Lei Jin, Ronghua Shi, Jinming Li, Yan Wang, Li Zhang, Chao-Zhao Liang, Vinod K Narayana, David P De Souza, Rick F Thorne, Li Rong Zhang, Xu Dong Zhang, Mian Wu.
      Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.
    Keywords:  c-Myc; glycoLINC; glycolytic complex; metabolon; serine starvation
    DOI:  https://doi.org/10.1016/j.molcel.2021.11.017
  31. Trends Endocrinol Metab. 2022 Jan 19. pii: S1043-2760(21)00301-5. [Epub ahead of print]
    Eukaryotic lipid droplets: metabolic hubs, and immune first responders.
    Marta Bosch, Albert Pol.
      As major eukaryotic lipid storage organelles, lipid droplets (LDs) are metabolic hubs coordinating energy flux and building block distribution. Infectious pathogens often promote accumulation and physically interact with LDs. The most accepted view is that host LDs are hijacked by invaders to draw on nutrients for host colonisation. However, unique traits such as biogenesis plasticity, dynamic proteome, signalling capacity, and ability to interact with other organelles endow LDs with competencies to face complex biological challenges. Here, we focus on published data suggesting that LDs are not usurped organelles but innate immunity first responders. By comparison with analogous mechanisms activated on LDs in nutrient-poor environments, our review supports the hypothesis that host LDs actively participate in immunometabolism, immune signalling, and microbial killing.
    Keywords:  infection; innate immunity; lipid droplet; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2021.12.006
  32. Nat Commun. 2022 Jan 27. 13(1): 546
    Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis.
    Bram Van den Bergh, Hannah Schramke, Joran Elie Michiels, Tom E P Kimkes, Jakub Leszek Radzikowski, Johannes Schimpf, Silke R Vedelaar, Sabrina Burschel, Liselot Dewachter, Nikola Lončar, Alexander Schmidt, Tim Meijer, Maarten Fauvart, Thorsten Friedrich, Jan Michiels, Matthias Heinemann.
      Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Perturbations of metabolic homeostasis can promote antibiotic persistence, but the precise mechanisms are not well understood. Here, we use laboratory evolution, population-wide sequencing and biochemical characterizations to identify mutations in respiratory complex I and discover how they promote persistence in Escherichia coli. We show that persistence-inducing perturbations of metabolic homeostasis are associated with cytoplasmic acidification. Such cytoplasmic acidification is further strengthened by compromised proton pumping in the complex I mutants. While RpoS regulon activation induces persistence in the wild type, the aggravated cytoplasmic acidification in the complex I mutants leads to increased persistence via global shutdown of protein synthesis. Thus, we propose that cytoplasmic acidification, amplified by a compromised complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.
    DOI:  https://doi.org/10.1038/s41467-022-28141-x
  33. Genome Biol. 2022 Jan 26. 23(1): 35
    Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource.
    Lisa Dressler, Michele Bortolomeazzi, Mohamed Reda Keddar, Hrvoje Misetic, Giulia Sartini, Amelia Acha-Sagredo, Lucia Montorsi, Neshika Wijewardhane, Dimitra Repana, Joel Nulsen, Jacki Goldman, Marc Pollitt, Patrick Davis, Amy Strange, Karen Ambrose, Francesca D Ciccarelli.
       BACKGROUND: Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development.
    RESULTS: Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation.
    CONCLUSIONS: Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/ .
    Keywords:  Cancer initiation; Driver genes; Somatic evolution; Systems-level properties
    DOI:  https://doi.org/10.1186/s13059-022-02607-z
  34. Cell Rep Methods. 2021 Dec 20. pii: 100132. [Epub ahead of print]1(8):
    Macrophage calcium reporter mice reveal immune cell communication in vitro and in vivo.
    Nika Taghdiri, David M Calcagno, Zhenxing Fu, Kenneth Huang, Rainer H Kohler, Ralph Weissleder, Todd P Coleman, Kevin R King.
      Cell communication underlies emergent functions in diverse cell types and tissues. Recent evidence suggests that macrophages are organized in communicating networks, but new tools are needed to quantitatively characterize the resulting cellular conversations. Here, we infer cell communication from spatiotemporal correlations of intracellular calcium dynamics that are non-destructively imaged across cell populations expressing genetically encoded calcium indicators. We describe a hematopoietic calcium reporter mouse (Csf1rCreGCaMP5fl) and a computational analysis pipeline for inferring communication between reporter cells based on "excess synchrony." We observed signals suggestive of cell communication in macrophages treated with immune-stimulatory DNA in vitro and tumor-associated immune cells imaged in a dorsal window chamber model in vivo. Together, the methods described here expand the toolkit for discovery of cell communication events in macrophages and other immune cells.
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100132
  35. Biochim Biophys Acta Mol Basis Dis. 2022 Jan 20. pii: S0925-4439(22)00017-5. [Epub ahead of print]1868(4): 166354
    Intersection of autophagy regulation and circadian rhythms in the heart.
    Inna Rabinovich-Nikitin, Matthew Love, Lorrie A Kirshenbaum.
      Autophagy is a vital cellular mechanism that controls the removal of damaged or dysfunctional cellular components. Autophagy allows the degradation and recycling of damaged proteins and organelles into their basic constituents of amino acids and fatty acids for cellular energy production. Under basal conditions, autophagy is essential for the maintenance of cell homeostasis and function. However, during cell stress, excessive activation of autophagy can be destructive and lead to cell death. Autophagy plays a crucial role in the cardiovascular system and helps to maintain normal cardiac function. During ischemia- reperfusion, autophagy can be adaptive or maladaptive depending on the timing and extent of activation. In this review, we highlight the molecular mechanisms and signaling pathways that underlie autophagy in response to cardiac stress and therapeutic approaches to modulate autophagy by pharmacological interventions. Finally, we also discuss the intersection between autophagy and circadian regulation in the heart. Understanding the mechanisms that underlie autophagy following cardiac injury can be translated to clinical cardiology use toward improved patient treatment and outcomes.
    Keywords:  Autophagy; Cardiovascular disease; Circadian rhythm; Mitochondria; mTOR
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166354
  36. Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01799-X. [Epub ahead of print]38(4): 110284
    Macrophages activated by hepatitis B virus have distinct metabolic profiles and suppress the virus via IL-1β to downregulate PPARα and FOXO3.
    Yumei Li, Yanwen Zhu, Shu Feng, Yuji Ishida, Tsu-Pei Chiu, Takeshi Saito, Sean Wang, David K Ann, Jing-Hsiung James Ou.
      Macrophages display phenotypic plasticity and can be induced by hepatitis B virus (HBV) to undergo either M1-like pro-inflammatory or M2-like anti-inflammatory polarization. Here, we report that M1-like macrophages stimulated by HBV exhibit a strong HBV-suppressive effect, which is diminished in M2-like macrophages. Transcriptomic analysis reveals that HBV induces the expression of interleukin-1β (IL-1β) in M1-like macrophages, which display a high oxidative phosphorylation (OXPHOS) activity distinct from that of conventional M1-like macrophages. Further analysis indicates that OXPHOS attenuates the expression of IL-1β, which suppresses the expression of peroxisome proliferator-activated receptor α (PPARα) and forkhead box O3 (FOXO3) in hepatocytes to suppress HBV gene expression and replication. Moreover, multiple HBV proteins can induce the expression of IL-1β in macrophages. Our results thus indicate that macrophages can respond to HBV by producing IL-1β to suppress HBV replication. However, HBV can also metabolically reprogram macrophages to enhance OXPHOS to minimize this host antiviral response.
    Keywords:  IL-1β signaling; M1-like and M2-like macrophages; hepatitis B virus; metabolic reprogramming; oxidative phosphorylation; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.celrep.2021.110284
  37. Nat Commun. 2022 Jan 24. 13(1): 457
    Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development.
    Margaret E Magaletta, Macrina Lobo, Eric M Kernfeld, Hananeh Aliee, Jack D Huey, Teagan J Parsons, Fabian J Theis, René Maehr.
      Maldevelopment of the pharyngeal endoderm, an embryonic tissue critical for patterning of the pharyngeal region and ensuing organogenesis, ultimately contributes to several classes of human developmental syndromes and disorders. Such syndromes are characterized by a spectrum of phenotypes that currently cannot be fully explained by known mutations or genetic variants due to gaps in characterization of critical drivers of normal and dysfunctional development. Despite the disease-relevance of pharyngeal endoderm, we still lack a comprehensive and integrative view of the molecular basis and gene regulatory networks driving pharyngeal endoderm development. To close this gap, we apply transcriptomic and chromatin accessibility single-cell sequencing technologies to generate a multi-omic developmental resource spanning pharyngeal endoderm patterning to the emergence of organ-specific epithelia in the developing mouse embryo. We identify cell-type specific gene regulation, distill GRN models that define developing organ domains, and characterize the role of an immunodeficiency-associated forkhead box transcription factor.
    DOI:  https://doi.org/10.1038/s41467-022-28067-4
  38. Cell Rep. 2022 Jan 25. pii: S2211-1247(22)00014-6. [Epub ahead of print]38(4): 110302
    Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription.
    Liping Yang, Shengchuan Chen, Qun Zhao, Chaohu Pan, Linan Peng, Yu Han, Lili Li, Jiayin Ruan, Jingyan Xia, Heng Yang, Feng Xu, Genhong Cheng.
      It is well known that interferon (IFN)-α/-β activates the JAK/STAT signaling pathway and suppresses viral replication through the induction of IFN stimulated genes (ISGs). Here, we report that knockout of HDAC3 from macrophages results in the decreased expression of STAT1 and STAT2, leading to defective antiviral immunity in cells and mice. Further studies show that HDAC3 interacts with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localizes with FOXK1 at the promoter of STAT1 and STAT2, and is required for protecting FOXK1 from lysosomal system-mediated degradation. FOXK1-deficient macrophages also show low STAT1 and STAT2 expression with defective responses to viruses. Thus, our studies uncover the biological importance of HDAC3 in regulating the antiviral immunity of macrophages through interacting with FOXK1 to regulate the expression of STAT1 and STAT2.
    Keywords:  FOXK1; HDAC3; STAT1; STAT2; transcription regulation; type I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2022.110302
  39. J Inherit Metab Dis. 2022 Jan 25.
    Medium branched chain fatty acids improve the profile of tricarboxylic acid cycle intermediates in mitochondrial fatty acid β-oxidation deficient cells: A comparative study.
    Anuradha Karunanidhi, Clinton Van't Land, Dhivyaa Rajasundaram, Mateus Grings, Jerry Vockley, Al-Walid Mohsen.
      Inherited errors of mitochondrial fatty acid β-oxidation (FAO) are life threatening, even with optimum care. FAO is the major source of energy for heart and is critical for skeletal muscles especially during physiologic stress. Clinical trials revealed that triheptanoin (commercially known as DojolviTM ; C7G), improved heart function and decreased hypoglycemia in long chain FAO disorders, but other symptoms including rhabdomyolysis persisted, suggesting suboptimal tissue distribution/utilization of heptanoic acid (C7) conjugates and/or rapid liver breakdown. In this study medium branched chain fatty acids were tested as potential anaplerotic treatments in fibroblasts from patients deficient in very long chain acyl-CoA dehydrogenase (VLCAD), long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), trifunctional protein (TFP), and carnitine palmitoyltransferase II (CPT II). Cells were cultured to near confluency and treated with C7, 2,6-dimethylheptanoic acid (dMC7), 6-amino-2,4-dimethylheptanoic acid (AdMC7), or 4,8-dimethylnonanoic acid (dMC9) for 72 hours and targeted metabolomics performed. The profile of TCA cycle intermediates was improved in cells treated with these branched chain fatty acids compared to C7. Intracellular propionate was higher in AdMC7 treated cells compared to C7 in VLCAD, LCHAD, and TFP deficient cell lines. With AdMC7 treatment, succinate was higher in CPT II and VLCAD deficient cells, compared to C7. Malate and glutamate were consistently higher in AdMC7 treated VLCAD, LCHAD, TFP, and CPT II deficient cells compared to the C7 treatment. The results provide the impetus to further evaluate and consider branched chain fatty acids as viable anaplerotic therapy for fatty acid oxidation disorders and other diseases. This article is protected by copyright. All rights reserved.
    Keywords:  CPT II deficiency; DojolviTM; LC-FAOD; LCHAD deficiency; MCT oil; TFP deficiency; VLCAD deficiency; long chain fatty acid oxidation disorders; medium branched chain fatty acids; triheptanoin
    DOI:  https://doi.org/10.1002/jimd.12480
  40. Front Immunol. 2021 ;12 797091
    Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.
    Dan He, Qiangdongzi Mao, Jialin Jia, Zhiyu Wang, Yu Liu, Tingting Liu, Bangwei Luo, Zhiren Zhang.
      The efficient removal of apoptotic cells (ACs), a process termed as efferocytosis, is essential for immune homeostasis. While recent work has established an important interplay between efferocytosis and cellular metabolic changing, underlying mechanisms remain poorly known. Here, we discovered that pentose phosphate pathway (PPP) regulates tolerogenic ACs clearance and immune tolerance. ACs decreased levels of PPP-related genes and metabolites in macrophages. AG1, the agonist of PPP, increased the activity of PPP but greatly reduced macrophage phagocytosis of ACs and enhanced the inflammatory response during efferocytosis. miR-323-5p regulated the expression of PPP-related genes and its levels increased during efferocytosis. miR-323-5p inhibitor greatly promoted levels of PPP-related genes, reduced the macrophage phagocytosis of ACs, and increased inflammatory response during efferocytosis, suggesting that miR-323-5p was essential in regulating PPP activity and ACs clearance in macrophages. Correspondingly, the PPP agonist AG1 exacerbated the lupus-like symptoms in the AC-induced systemic lupus erythematosus (SLE) model. Our study reveals that regulating PPP-dependent metabolic reprogramming is critical for tolerogenic ACs phagocytosis and immune tolerance.
    Keywords:  autoimmune disease; efferocytosis; immune tolerance; macrophage; pentose phosphate pathway (PPP)
    DOI:  https://doi.org/10.3389/fimmu.2021.797091
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