bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022‒09‒04
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
  2. Mitochondrial DNA is a major source of driver mutations in cancer.
  3. Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2.
  4. The human mitochondrial genome contains a second light strand promoter.
  5. Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization.
  6. Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
  7. Mitochondria in cancer: clean windmills or stressed tinkerers?
  8. Author Correction: PHGDH heterogeneity potentiates cancer cell dissemination and metastasis.
  9. Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response.
  10. Operation of a TCA cycle subnetwork in the mammalian nucleus.
  11. NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling.
  12. Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing.
  13. Sublethal cytochrome c release generates drug-tolerant persister cells.
  14. Methionine cycle-dependent regulation of T cells in cancer immunity.
  15. Investigating the role of GLUL as a survival factor in cellular adaptation to glutamine depletion via targeted stable isotope resolved metabolomics.
  16. Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function.
  17. Gut bacterial nutrient preferences quantified in vivo.
  18. Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
  19. L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.
  20. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
  21. Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
  22. Non-degradable autophagic vacuoles are indispensable for cell competition.
  23. Distinct metabolic states guide maturation of inflammatory and tolerogenic dendritic cells.
  24. PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability.
  25. Maintenance of small molecule redox homeostasis in mitochondria.
  26. The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases.
  27. Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
  28. Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT.
  29. Cancer cell histone density links global histone acetylation, mitochondrial proteome and histone acetylase inhibitor sensitivity.
  30. Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity.
  31. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
  32. PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis.
  33. USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer.
  34. SLC4A7 and mTORC1 raise nucleotide synthesis with bicarbonate.
  35. AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
  36. Branched-chain amino acids and mitochondrial biogenesis: an overview and mechanistic summary.
  37. Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.
  38. Editorial: Mitochondria as a hub in cellular signaling.
  39. MIRTH: Metabolite Imputation via Rank-Transformation and Harmonization.
  40. Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.
  41. Brain endothelial STING1 activation by Plasmodium-sequestered heme promotes cerebral malaria via type I IFN response.
  42. The Warburg effect: Saturation of mitochondrial NADH shuttles triggers aerobic lactate fermentation.
  43. Identification of two pathways mediating protein targeting from ER to lipid droplets.
  44. The elevated D-2-hydroxyglutarate level found as a characteristic metabolic change of colon cancer in both in vitro and in vivo models.
  45. Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
  46. Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.
  1. Sci Adv. 2022 Sep 02. 8(35): eabn9550
    In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.
    Panayotis Pachnis, Zheng Wu, Brandon Faubert, Alpaslan Tasdogan, Wen Gu, Spencer Shelton, Ashley Solmonson, Aparna D Rao, Akash K Kaushik, Thomas J Rogers, Jessalyn M Ubellacker, Collette A LaVigne, Chendong Yang, Bookyung Ko, Vijayashree Ramesh, Jessica Sudderth, Lauren G Zacharias, Misty S Martin-Sandoval, Duyen Do, Thomas P Mathews, Zhiyu Zhao, Prashant Mishra, Sean J Morrison, Ralph J DeBerardinis.
      In mice and humans with cancer, intravenous 13C-glucose infusion results in 13C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD+ by the ETC. However, 13C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD+ independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13C labeling from multiple nutrients.
    DOI:  https://doi.org/10.1126/sciadv.abn9550
  2. Trends Cancer. 2022 Aug 27. pii: S2405-8033(22)00172-8. [Epub ahead of print]
    Mitochondrial DNA is a major source of driver mutations in cancer.
    Minsoo Kim, Mahnoor Mahmood, Ed Reznik, Payam A Gammage.
      Mitochondrial DNA (mtDNA) mutations are among the most common genetic events in all tumors and directly impact metabolic homeostasis. Despite the central role mitochondria play in energy metabolism and cellular physiology, the role of mutations in the mitochondrial genomes of tumors has been contentious. Until recently, genomic and functional studies of mtDNA variants were impeded by a lack of adequate tumor mtDNA sequencing data and available methods for mitochondrial genome engineering. These barriers and a conceptual fog surrounding the functional impact of mtDNA mutations in tumors have begun to lift, revealing a path to understanding the role of this essential metabolic genome in cancer initiation and progression. Here we discuss the history, recent developments, and challenges that remain for mitochondrial oncogenetics as the impact of a major new class of cancer-associated mutations is unveiled.
    Keywords:  cancer; genome editing; mitochondrial DNA; mutation selection
    DOI:  https://doi.org/10.1016/j.trecan.2022.08.001
  3. Biochim Biophys Acta Mol Basis Dis. 2022 Aug 26. pii: S0925-4439(22)00201-0. [Epub ahead of print] 166530
    Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2.
    Alexander Heinz, Yannic Nonnenmacher, Antonia Henne, Michelle-Amirah Khalil, Ketlin Bejkollari, Catherine Dostert, Shirin Hosseini, Oliver Goldmann, Wei He, Roberta Palorini, Charlène Verschueren, Martin Korte, Ferdinando Chiaradonna, Eva Medina, Dirk Brenner, Karsten Hiller.
      Macrophages undergo extensive metabolic reprogramming during classical pro-inflammatory polarization (M1-like). The accumulation of itaconate has been recognized as both a consequence and mediator of the inflammatory response. In this study we first examined the specific functions of itaconate inside fractionated mitochondria. We show that M1 macrophages produce itaconate de novo via aconitase decarboxylase 1 (ACOD1) inside mitochondria. The carbon for this reaction is not only supplied by oxidative TCA cycling, but also through the reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase (IDH). While macrophages are capable of sustaining a certain degree of itaconate production during hypoxia by augmenting the activity of IDH-dependent reductive carboxylation, we demonstrate that sufficient itaconate synthesis requires a balance of reductive and oxidative TCA cycle metabolism in mouse macrophages. In comparison, human macrophages increase itaconate accumulation under hypoxic conditions by augmenting reductive carboxylation activity. We further demonstrated that itaconate attenuates reductive carboxylation at IDH2, restricting its own production and the accumulation of the immunomodulatory metabolites citrate and 2-hydroxyglutarate. In line with this, reductive carboxylation is enhanced in ACOD1-depleted macrophages. Mechanistically, the inhibition of IDH2 by itaconate is linked to the alteration of the mitochondrial NADP+/NADPH ratio and competitive succinate dehydrogenase inhibition. Taken together, our findings extend the current model of TCA cycle reprogramming during pro-inflammatory macrophage activation and identified novel regulatory properties of itaconate.
    Keywords:  2-hydroxyglutarate; Mitochondrial metabolism; Proinflammatory macrophage; Redox balance; Reductive carboxylation; TCA cycle
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166530
  4. Mol Cell. 2022 Aug 23. pii: S1097-2765(22)00764-X. [Epub ahead of print]
    The human mitochondrial genome contains a second light strand promoter.
    Benedict G Tan, Christian D Mutti, Yonghong Shi, Xie Xie, Xuefeng Zhu, Pedro Silva-Pinheiro, Katja E Menger, Héctor Díaz-Maldonado, Wei Wei, Thomas J Nicholls, Patrick F Chinnery, Michal Minczuk, Maria Falkenberg, Claes M Gustafsson.
      The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
    Keywords:  DdCBE; LSP2; POLRMT; light strand promoter; mitochondria; mitochondrial DNA; mitochondrial gene expression; mitochondrial promoter; mtDNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.011
  5. J Biol Chem. 2022 Aug 25. pii: S0021-9258(22)00861-4. [Epub ahead of print] 102418
    Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization.
    Mark L Sowers, Hui Tang, Vipul K Singh, Arshad Khan, Abhishek Mishra, Blanca I Restrepo, Chinnaswamy Jagannath, Kangling Zhang.
      Macrophages (MФ) are an essential immune cell for defense and repair that travel to different tissues and adapt based on local stimuli. A critical factor that may govern their polarization is the cross-talk between metabolism and epigenetics. However, simultaneous measurements of metabolites, epigenetics, and proteins (phenotype) has been a major technical challenge. To address this, we have developed a novel triomics approach using mass spectrometry to comprehensively analyze metabolites, proteins, and histone modifications, in a single sample. To demonstrate this technique, we investigated the metabolic-epigenetic-phenotype axis following polarization of human blood-derived monocytes into either 'pro-inflammatory M1'- or 'anti-inflammatory M2-' MФs. We report here a complex relationship between arginine, tryptophan, glucose, and the citric acid cycle (TCA) metabolism, protein and histone post-translational modifications, and human macrophage polarization that was previously not described. Surprisingly, M1-MФs had globally reduced histone acetylation levels but high levels of acetylated amino acids. This suggests acetyl-CoA was diverted, in part, towards acetylated amino acids. Consistent with this, stable isotope tracing of glucose revealed reduced usage of acetyl-CoA for histone acetylation in M1-MФs. Furthermore, isotope tracing also revealed MФs uncoupled glycolysis from the TCA cycle, as evidenced by poor isotope enrichment of succinate. M2-MФs had high levels of kynurenine and serotonin which are reported to have immune-suppressive effects. Kynurenine is upstream of de novo NAD+ metabolism which is a necessary cofactor for Sirtuin-type histone deacetylases. Taken together, we demonstrate a complex interplay between metabolism and epigenetics that may ultimately influence cell phenotype.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102418
  6. J Cell Biol. 2022 Oct 03. pii: e202206140. [Epub ahead of print]221(10):
    Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
    Yvette C Wong, Soojin Kim, Jasmine Cisneros, Catherine G Molakal, Pingping Song, Steven J Lubbe, Dimitri Krainc.
      Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson's disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy-linked mutant Mid51, which does not inhibit Mid51/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria-lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.
    DOI:  https://doi.org/10.1083/jcb.202206140
  7. Trends Cell Biol. 2022 Aug 18. pii: S0962-8924(22)00191-X. [Epub ahead of print]
    Mitochondria in cancer: clean windmills or stressed tinkerers?
    Dario C Altieri.
      There is now a consensus that mitochondria are important tumor drivers, sophisticated biological machines that can engender a panoply of key disease traits. How this happens, however, is still mostly elusive. The opinion presented here is that what cancer exploits are not the normal mitochondria of oxygenated and nutrient-replete tissues, but the unfit, damaged, and dysfunctional organelles generated by the hostile environment of tumor growth. These 'ghost' mitochondria survive quality control and thwart cell death to relay multiple comprehensive 'danger signals' of metabolic starvation, cellular stress, and reprogrammed gene expression. The result is a new, treacherous cellular phenotype, proliferatively quiescent but highly motile, that enables tumor cell escape from a threatening environment and colonization of distant, more favorable sites (metastasis).
    Keywords:  Mic60; metabolism; metastasis; mitochondria; tumor plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2022.08.001
  8. Nature. 2022 Aug 30.
    Author Correction: PHGDH heterogeneity potentiates cancer cell dissemination and metastasis.
    Matteo Rossi, Patricia Altea-Manzano, Margherita Demicco, Ginevra Doglioni, Laura Bornes, Marina Fukano, Anke Vandekeere, Alejandro M Cuadros, Juan Fernández-García, Carla Riera-Domingo, Cristina Jauset, Mélanie Planque, H Furkan Alkan, David Nittner, Dongmei Zuo, Lindsay A Broadfield, Sweta Parik, Antonino Alejandro Pane, Francesca Rizzollo, Gianmarco Rinaldi, Tao Zhang, Shao Thing Teoh, Arin B Aurora, Panagiotis Karras, Ines Vermeire, Dorien Broekaert, Joke Van Elsen, Maximilian M L Knott, Martin F Orth, Sofie Demeyer, Guy Eelen, Lacey E Dobrolecki, Ayse Bassez, Thomas Van Brussel, Karl Sotlar, Michael T Lewis, Harald Bartsch, Manfred Wuhrer, Peter van Veelen, Peter Carmeliet, Jan Cools, Sean J Morrison, Jean-Christophe Marine, Diether Lambrechts, Massimiliano Mazzone, Gregory J Hannon, Sophia Y Lunt, Thomas G P Grünewald, Morag Park, Jacco van Rheenen, Sarah-Maria Fendt.
      
    DOI:  https://doi.org/10.1038/s41586-022-05226-7
  9. Signal Transduct Target Ther. 2022 Sep 01. 7(1): 303
    Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response.
    Hao Zeng, Ting Pan, Meiling Zhan, Renaguli Hailiwu, Baolin Liu, Hua Yang, Ping Li.
      Endothelial-to-mesenchymal transition (EndoMT), the process wherein endothelial cells lose endothelial identity and adopt mesenchymal-like phenotypes, constitutes a critical contributor to cardiac fibrosis. The phenotypic plasticity of endothelial cells can be intricately shaped by alteration of metabolic pathways, but how endothelial cells adjust cellular metabolism to drive EndoMT is incompletely understood. Here, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a critical driver of EndoMT via triggering abnormal glycolysis and compromising mitochondrial respiration. Pharmacological suppression of PFKFB3 with salvianolic acid C (SAC), a phenolic compound derived from Salvia miltiorrhiza, attenuates EndoMT and fibrotic response. PFKFB3-haplodeficiency recapitulates the anti-EndoMT effect of SAC while PFKFB3-overexpression augments the magnitude of EndoMT and exacerbates cardiac fibrosis. Mechanistically, PFKFB3-driven glycolysis compromises cytoplasmic nicotinamide adenine dinucleotide phosphate (reduced form, NADPH) production via hijacking glucose flux from pentose phosphate pathway. Efflux of mitochondrial NADPH through isocitrate/α-ketoglutarate shuttle replenishes cytoplasmic NADPH pool but meanwhile impairs mitochondrial respiration by hampering mitochondrial iron-sulfur cluster biosynthesis. SAC disrupts PFKFB3 stability by accelerating its degradation and thus maintains metabolic homeostasis in endothelial cells, underlying its anti-EndoMT effects. These findings for the first time identify the critical role of PFKFB3 in triggering EndoMT by driving abnormal glycolysis in endothelial cells, and also highlight the therapeutic potential for pharmacological intervention of PFKFB3 (with SAC or other PFKFB3 inhibitors) to combat EndoMT-associated fibrotic responses via metabolic regulation.
    DOI:  https://doi.org/10.1038/s41392-022-01097-6
  10. Sci Adv. 2022 Sep 02. 8(35): eabq5206
    Operation of a TCA cycle subnetwork in the mammalian nucleus.
    Eleni Kafkia, Amparo Andres-Pons, Kerstin Ganter, Markus Seiler, Tom S Smith, Anna Andrejeva, Paula Jouhten, Filipa Pereira, Catarina Franco, Anna Kuroshchenkova, Sergio Leone, Ritwick Sawarkar, Rebecca Boston, James Thaventhiran, Judith B Zaugg, Kathryn S Lilley, Christophe Lancrin, Martin Beck, Kiran Raosaheb Patil.
      Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.
    DOI:  https://doi.org/10.1126/sciadv.abq5206
  11. Nat Cell Biol. 2022 Sep 01.
    NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling.
    Sachin Verma, David Crawford, Ali Khateb, Yongmei Feng, Eduard Sergienko, Gaurav Pathria, Chen-Ting Ma, Steven H Olson, David Scott, Rabi Murad, Eytan Ruppin, Michael Jackson, Ze'ev A Ronai.
      Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1. The transcription factor NRF2 mediates GCDH-dependent melanoma cell death programmes. Mechanistically, GCDH knockdown induces NRF2 glutarylation, increasing its stability and DNA binding activity, with a concomitant transcriptional upregulation of ATF4, ATF3, DDIT3 and CHAC1, resulting in cell death. In vivo, inducible inactivation of GCDH effectively inhibited melanoma tumour growth. Correspondingly, reduced GCDH expression correlated with improved survival of patients with melanoma. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signalling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.
    DOI:  https://doi.org/10.1038/s41556-022-00985-x
  12. Commun Biol. 2022 Sep 02. 5(1): 900
    Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing.
    Christopher J Groten, Brian A MacVicar.
      Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD+ to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.
    DOI:  https://doi.org/10.1038/s42003-022-03848-1
  13. Cell. 2022 Sep 01. pii: S0092-8674(22)00978-3. [Epub ahead of print]185(18): 3356-3374.e22
    Sublethal cytochrome c release generates drug-tolerant persister cells.
    Halime Kalkavan, Mark J Chen, Jeremy C Crawford, Giovanni Quarato, Patrick Fitzgerald, Stephen W G Tait, Colin R Goding, Douglas R Green.
      Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.
    Keywords:  ATF4; Bcl-2 family; GPX4; HRI; ferroptosis; persister integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2022.07.025
  14. Front Oncol. 2022 ;12 969563
    Methionine cycle-dependent regulation of T cells in cancer immunity.
    Tian Zhao, Julian J Lum.
      The methionine cycle comprises a series of reactions that catabolizes and regenerates methionine. This process is crucial to many cellular functions, including polyamine synthesis, DNA synthesis, redox balance, and DNA and histone methylation. In response to antigens, T cells activate the methionine cycle to support proliferation and differentiation, indicating the importance of the methionine cycle to T cell immunity. In cancer, T cells serve as important effectors of adaptive immunity by directly killing cancerous cells. However, the tumor microenvironment can induce a state of T cell exhaustion by regulating the methionine metabolism of T cells, posing a barrier to both endogenous T cell responses and T cell immunotherapy. Here we review the role of methionine cycle metabolites in regulating the activation and effector function of T cells and explore the mechanism by which tumor cells exploit the methionine pathway as a means of immune evasion. Finally, we discuss new perspectives on reprogramming the methionine cycle of T cells to enhance anti-tumor immunotherapy.
    Keywords:  T cells; cancer; cancer immunotherapy; immunemetabolism; metabolism; the methionine cycle
    DOI:  https://doi.org/10.3389/fonc.2022.969563
  15. Front Mol Biosci. 2022 ;9 859787
    Investigating the role of GLUL as a survival factor in cellular adaptation to glutamine depletion via targeted stable isotope resolved metabolomics.
    Șafak Bayram, Yasmin Sophiya Razzaque, Sabrina Geisberger, Matthias Pietzke, Susanne Fürst, Carolina Vechiatto, Martin Forbes, Guido Mastrobuoni, Stefan Kempa.
      Cellular glutamine synthesis is thought to be an important resistance factor in protecting cells from nutrient deprivation and may also contribute to drug resistance. The application of ‟targeted stable isotope resolved metabolomics" allowed to directly measure the activity of glutamine synthetase in the cell. With the help of this method, the fate of glutamine derived nitrogen within the biochemical network of the cells was traced. The application of stable isotope labelled substrates and analyses of isotope enrichment in metabolic intermediates allows the determination of metabolic activity and flux in biological systems. In our study we used stable isotope labelled substrates of glutamine synthetase to demonstrate its role in the starvation response of cancer cells. We applied 13C labelled glutamate and 15N labelled ammonium and determined the enrichment of both isotopes in glutamine and nucleotide species. Our results show that the metabolic compensatory pathways to overcome glutamine depletion depend on the ability to synthesise glutamine via glutamine synthetase. We demonstrate that the application of dual-isotope tracing can be used to address specific reactions within the biochemical network directly. Our study highlights the potential of concurrent isotope tracing methods in medical research.
    Keywords:  GLUL; cancer metabolism; glutamine addiction; glutamine synthetase; nucleotide biosynthesis; targeted stable isotope resolved metabolomics
    DOI:  https://doi.org/10.3389/fmolb.2022.859787
  16. Blood Adv. 2022 Aug 31. pii: bloodadvances.2022008242. [Epub ahead of print]
    Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function.
    Yoshikane Kikushige, Toshihiro Miyamoto, Yu Kochi, Yuichiro Semba, Maki Ohishi, Hidetoshi Irifune, Kiwamu Hatakeyama, Yuya Kunisaki, Takeshi Sugio, Teppei Sakoda, Kohta Miyawaki, Koji Kato, Tomoyoshi Soga, Koichi Akashi.
      Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia-specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), and primary human acute myelogenous leukemia (AML) and lymphoblastic leukemia (ALL) cells. Here we show that human leukemia addicts to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG) and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids (BCKAs), whose metabolic processes provide leukemia cells with critical substrates for the TCA cycle and the non-essential amino acids synthesis, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates polycomb repressive complex 2 (PRC2) function, an epigenetic regulator for stem cell signatures, through inhibiting transcription of PRC components, such as zeste homolog 2 (EZH2) and embryonic ectoderm development (EED). Accordingly, BCAA catabolism plays an important role in maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008242
  17. Cell. 2022 Sep 01. pii: S0092-8674(22)00923-0. [Epub ahead of print]185(18): 3441-3456.e19
    Gut bacterial nutrient preferences quantified in vivo.
    Xianfeng Zeng, Xi Xing, Meera Gupta, Felix C Keber, Jaime G Lopez, Ying-Chiang J Lee, Asael Roichman, Lin Wang, Michael D Neinast, Mohamed S Donia, Martin Wühr, Cholsoon Jang, Joshua D Rabinowitz.
      Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
    Keywords:  diet; host-microbiome interactions; isotope tracing; metabolism; metabolomics; methodology; mice; microbiome; nutrient; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2022.07.020
  18. Nat Commun. 2022 Aug 30. 13(1): 5100
    Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
    Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.
      Human mitochondrial gene expression relies on the specific recognition and aminoacylation of mitochondrial tRNAs (mtRNAs) by nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Despite their essential role in cellular energy homeostasis, strong mutation pressure and genetic drift have led to an unparalleled sequence erosion of animal mtRNAs. The structural and functional consequences of this erosion are not understood. Here, we present cryo-EM structures of the human mitochondrial seryl-tRNA synthetase (mSerRS) in complex with mtRNASer(GCU). These structures reveal a unique mechanism of substrate recognition and aminoacylation. The mtRNASer(GCU) is highly degenerated, having lost the entire D-arm, tertiary core, and stable L-shaped fold that define canonical tRNAs. Instead, mtRNASer(GCU) evolved unique structural innovations, including a radically altered T-arm topology that serves as critical identity determinant in an unusual shape-selective readout mechanism by mSerRS. Our results provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41467-022-32544-1
  19. Circ Res. 2022 Aug 31. 101161CIRCRESAHA122321227
    L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.
    Huamei He, Ryan M Mulhern, William M Oldham, Wusheng Xiao, Yi-Dong Lin, Ronglih Liao, Joseph Loscalzo.
      BACKGROUND: L-2-hydroxyglutarate (L2HG) couples mitochondrial and cytoplasmic energy metabolism to support cellular redox homeostasis. Under oxygen-limiting conditions, mammalian cells generate L2HG to counteract the adverse effects of reductive stress induced by hypoxia. Very little is known, however, about whether and how L2HG provides tissue protection from redox stress during low-flow ischemia (LFI) and ischemia-reperfusion injury. We examined the cardioprotective effects of L2HG accumulation against LFI and ischemia-reperfusion injury and its underlying mechanism using genetic mouse models.METHODS AND RESULTS: L2HG accumulation was induced by homozygous (L2HGDH [L-2-hydroxyglutarate dehydrogenase]-/-) or heterozygous (L2HGDH+/-) deletion of the L2HGDH gene in mice. Hearts isolated from these mice and their wild-type littermates (L2HGDH+/+) were subjected to baseline perfusion or 90-minute LFI or 30-minute no-flow ischemia followed by 60- or 120-minute reperfusion. Using [13C]- and [31P]-NMR spectroscopy, high-performance liquid chromatography, real-time quantitative real-time polymerase chain reaction, ELISA, triphenyltetrazolium staining, colorimetric/fluorometric spectroscopy, and echocardiography, we found that L2HGDH deletion induces L2HG accumulation at baseline and under stress conditions with significant functional consequences. In response to LFI or ischemia-reperfusion, L2HG accumulation shifts glucose flux from glycolysis towards the pentose phosphate pathway. These key metabolic changes were accompanied by enhanced cellular reducing potential, increased elimination of reactive oxygen species, attenuated oxidative injury and myocardial infarction, preserved cellular energy state, and improved cardiac function in both L2HGDH-/- and L2HGDH+/- hearts compared with L2HGDH+/+ hearts under ischemic stress conditions.
    CONCLUSION: L2HGDH deletion-induced L2HG accumulation protects against myocardial injury during LFI and ischemia-reperfusion through a metabolic shift of glucose flux from glycolysis towards the pentose phosphate pathway. L2HG offers a novel mechanism for eliminating reactive oxygen species from myocardial tissue, mitigating redox stress, reducing myocardial infarct size, and preserving high-energy phosphates and cardiac function. Targeting L2HG levels through L2HGDH activity may serve as a new therapeutic strategy for cardiovascular diseases related to oxidative injury.
    Keywords:  glycolysis; ischemia; pentose phosphate pathway; reactive oxygen species; reperfusion
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321227
  20. Am J Hum Genet. 2022 Sep 01. pii: S0002-9297(22)00311-1. [Epub ahead of print]109(9): 1692-1712
    Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
    Rauan Kaiyrzhanov, Sami E M Mohammed, Reza Maroofian, Ralf A Husain, Alessia Catania, Alessandra Torraco, Ahmad Alahmad, Marina Dutra-Clarke, Sabine Grønborg, Annapurna Sudarsanam, Julie Vogt, Filippo Arrigoni, Julia Baptista, Shahzad Haider, René G Feichtinger, Paolo Bernardi, Alessandra Zulian, Mirjana Gusic, Stephanie Efthymiou, Renkui Bai, Farah Bibi, Alejandro Horga, Julian A Martinez-Agosto, Amanda Lam, Andreea Manole, Diego-Perez Rodriguez, Romina Durigon, Angela Pyle, Buthaina Albash, Carlo Dionisi-Vici, David Murphy, Diego Martinelli, Enrico Bugiardini, Katrina Allis, Costanza Lamperti, Siegfried Reipert, Lotte Risom, Lucia Laugwitz, Michela Di Nottia, Robert McFarland, Laura Vilarinho, Michael Hanna, Holger Prokisch, Johannes A Mayr, Enrico Silvio Bertini, Daniele Ghezzi, Elsebet Østergaard, Saskia B Wortmann, Rosalba Carrozzo, Tobias B Haack, Robert W Taylor, Antonella Spinazzola, Karin Nowikovsky, Henry Houlden.
      Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.
    Keywords:  LETM1; Wolf-Hirschhorn syndrome; genetics; mitochondria; mitochondrial diseases; neurodegeneration; neurology; oxidative phosphorylation; potassium transport; volume homeostasis
    DOI:  https://doi.org/10.1016/j.ajhg.2022.07.007
  21. Cell Stem Cell. 2022 Sep 01. pii: S1934-5909(22)00346-0. [Epub ahead of print]29(9): 1287-1289
    Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
    Ji-Hyung Lee, Foteini Mourkioti.
      Muscle stem cells (MuSCs) exhibit different metabolic profiles depending on their activity, however the mechanisms by which mitochondria affect MuSC fate has been understudied. In this issue of Cell Stem Cell, Hong et al. (2022) and Baker et al. (2022) demonstrate that defects in mitochondrial dynamics hinder proper MuSC activation and impair muscle regeneration.
    DOI:  https://doi.org/10.1016/j.stem.2022.08.010
  22. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01112-3. [Epub ahead of print]40(9): 111292
    Non-degradable autophagic vacuoles are indispensable for cell competition.
    Eilma Akter, Yukihiro Tasaki, Yusuke Mori, Kazuki Nakai, Kazuki Hachiya, Hancheng Lin, Masamitsu Konno, Tomoko Kamasaki, Kenji Tanabe, Yumi Umeda, Shotaro Yamano, Yasuyuki Fujita, Shunsuke Kon.
      Cell competition is a process by which unwanted cells are eliminated from tissues. Apical extrusion is one mode whereby normal epithelial cells remove transformed cells, but it remains unclear how this process is mechanically effected. In this study, we show that autophagic and endocytic fluxes are attenuated in RasV12-transformed cells surrounded by normal cells due to lysosomal dysfunction, and that chemical manipulation of lysosomal activity compromises apical extrusion. We further find that RasV12 cells deficient in autophagy initiation machinery are resistant to elimination pressure exerted by normal cells, suggesting that non-degradable autophagic vacuoles are required for cell competition. Moreover, in vivo analysis revealed that autophagy-ablated RasV12 cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Collectively, our findings illuminate a positive role for autophagy in cell competition and reveal a homeostasis-preserving function of autophagy upon emergence of transformed cells.
    Keywords:  CP: Cell biology; autophagic flux; cell competition; lysosomal dysfunction; non-degradable autophagic vacuoles; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111292
  23. Nat Commun. 2022 Sep 02. 13(1): 5184
    Distinct metabolic states guide maturation of inflammatory and tolerogenic dendritic cells.
    Juraj Adamik, Paul V Munson, Felix J Hartmann, Alexis J Combes, Philippe Pierre, Matthew F Krummel, Sean C Bendall, Rafael J Argüello, Lisa H Butterfield.
      Cellular metabolism underpins immune cell functionality, yet our understanding of metabolic influences in human dendritic cell biology and their ability to orchestrate immune responses is poorly developed. Here, we map single-cell metabolic states and immune profiles of inflammatory and tolerogenic monocytic dendritic cells using recently developed multiparametric approaches. Single-cell metabolic pathway activation scores reveal simultaneous engagement of multiple metabolic pathways in distinct monocytic dendritic cell differentiation stages. GM-CSF/IL4-induce rapid reprogramming of glycolytic monocytes and transient co-activation of mitochondrial pathways followed by TLR4-dependent maturation of dendritic cells. Skewing of the mTOR:AMPK phosphorylation balance and upregulation of OXPHOS, glycolytic and fatty acid oxidation metabolism underpin metabolic hyperactivity and an immunosuppressive phenotype of tolerogenic dendritic cells, which exhibit maturation-resistance and a de-differentiated immune phenotype marked by unique immunoregulatory receptor signatures. This single-cell dataset provides important insights into metabolic pathways impacting the immune profiles of human dendritic cells.
    DOI:  https://doi.org/10.1038/s41467-022-32849-1
  24. Nat Commun. 2022 Aug 31. 13(1): 5118
    PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability.
    Benjamin P Hurrell, Doumet Georges Helou, Emily Howard, Jacob D Painter, Pedram Shafiei-Jahani, Arlene H Sharpe, Omid Akbari.
      Regulatory T (Treg) cells are central to limit immune responses to allergens. Here we show that PD-L2 deficiency prevents the induction of tolerance to ovalbumin and control of airway hyperreactivity, in particular by limiting pTreg numbers and function. In vitro, PD-1/PD-L2 interactions increase iTreg numbers and stability. In mice lacking PD-L2 we find lower numbers of splenic pTregs at steady state, producing less IL-10 upon activation and with reduced suppressive activity. Remarkably, the numbers of splenic pTregs are restored by adoptively transferring PD-L2high dendritic cells to PD-L2KO mice. Functionally, activated pTregs lacking PD-L2 show lower Foxp3 expression, higher methylation of the Treg-Specific Demethylation Region (TSDR) and a decreased Tricarboxylic Acid (TCA) cycle associated with a defect in mitochondrial function and ATP production. Consequently, pyruvate treatment of PD-L2KO mice partially restores IL-10 production and airway tolerance. Together, our study highlights the importance of the PD-1/PD-L2 axis in the control of metabolic pathways regulating pTreg Foxp3 stability and suppressive functions, opening up avenues to further improve mucosal immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-32899-5
  25. FEBS Lett. 2022 Aug 27.
    Maintenance of small molecule redox homeostasis in mitochondria.
    Lianne Jhc Jacobs, Jan Riemer.
      Compartmentalization of eukaryotic cells enables fundamental otherwise often incompatible cellular processes. Establishment and maintenance of distinct compartments in the cell relies on proteins, lipids and metabolites but also on small redox molecules. In particular, small redox molecules such as glutathione, NAD(P)H, and hydrogen peroxide (H2 O2 ) cooperate with protein partners in dedicated machineries to establish specific subcellular redox compartments with conditions that enable oxidative protein folding and redox signalling. Dysregulated redox homeostasis has been directly linked with a number of diseases including cancer, neurological disorders, cardiovascular diseases, obesity, metabolic diseases, and aging. In this review, we will summarize mechanisms regulating establishment and maintenance of redox homeostasis in the mitochondrial subcompartments of mammalian cells.
    Keywords:  compartmentalization; glutathione; hydrogen peroxide; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.14485
  26. Protein Sci. 2022 Sep;31(9): e4399
    The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases.
    Rubén M Buey, David Fernández-Justel, Alberto Jiménez, José L Revuelta.
      Inosine 5'-monophosphate dehydrogenase (IMPDH) is an evolutionarily conserved enzyme that mediates the first committed step in de novo guanine nucleotide biosynthetic pathway. It is an essential enzyme in purine nucleotide biosynthesis that modulates the metabolic flux at the branch point between adenine and guanine nucleotides. IMPDH plays key roles in cell homeostasis, proliferation, and the immune response, and is the cellular target of several drugs that are widely used for antiviral and immunosuppressive chemotherapy. IMPDH enzyme is tightly regulated at multiple levels, from transcriptional control to allosteric modulation, enzyme filamentation, and posttranslational modifications. Herein, we review recent developments in our understanding of the mechanisms of IMPDH regulation, including all layers of allosteric control that fine-tune the enzyme activity.
    Keywords:  IMP dehydrogenase; allosteric regulation; enzyme filamentation; protein structure and function; purine nucleotide biosynthesis
    DOI:  https://doi.org/10.1002/pro.4399
  27. Adv Sci (Weinh). 2022 Aug 28. e2201992
    Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
    Meng Tang, Hui Xu, Hongyan Huang, Hao Kuang, Chenxi Wang, Qinqin Li, Xin Zhang, Yizhong Ge, Mengmeng Song, Xi Zhang, Ziwen Wang, Chaobing Ma, Jinlin Kang, Wanfang Zhang, You Wang, Bo Zhang, Xiaowei Zhang, Yongbing Chen, Minghua Cong, Gerry Melino, Xiaobin Wang, Fuxiang Zhou, Qiang Sun, Hanping Shi.
      Although targeting cancer metabolism is a promising therapeutic strategy, clinical success depends on accurate molecular and metabolic subtyping. Here, this study reports two metabolism-based molecular subtypes associated with the ketogenic treatment of colon cancer: glycolytic (glycolysis+ /ketolysis- ) and ketolytic (glycolysis+ /ketolysis+ ), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone-containing interventions in vitro and in vivo. Notably, the glycolytic subtype is able to be transformed into the ketolytic subtype in p53-mutated tumors upon glucose limitation, rendering resistance to ketogenic therapy associated with upregulation of ketolytic enzymes, such as OXCT1 by mutant p53. The allosteric activator of mutant p53 effectively blocks the rewired molecular expression and the reprogrammed metabolism, leading to the suppression of tumor growth. The findings highlight the utility of metabolic subtyping to guide ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment.
    Keywords:  OXCT1; colon cancer; ketogenic therapy; metabolic subtype; p53
    DOI:  https://doi.org/10.1002/advs.202201992
  28. Front Oncol. 2022 ;12 976961
    Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT.
    Mostafa A Aboouf, Franco Guscetti, Nadine von Büren, Julia Armbruster, Hyrije Ademi, Maja Ruetten, Florinda Meléndez-Rodríguez, Thomas Rülicke, Alexander Seymer, Robert A Jacobs, Edith M Schneider Gasser, Julian Aragones, Drorit Neumann, Max Gassmann, Markus Thiersch.
      Erythropoietin receptor (EPOR) is widely expressed in healthy and malignant tissues. In certain malignancies, EPOR stimulates tumor growth. In healthy tissues, EPOR controls processes other than erythropoiesis, including mitochondrial metabolism. We hypothesized that EPOR also controls the mitochondrial metabolism in cancer cells. To test this hypothesis, we generated EPOR-knockdown cancer cells to grow tumor xenografts in mice and analyzed tumor cellular respiration via high-resolution respirometry. Furthermore, we analyzed cellular respiratory control, mitochondrial content, and regulators of mitochondrial biogenesis in vivo and in vitro in different cancer cell lines. Our results show that EPOR controls tumor growth and mitochondrial biogenesis in tumors by controlling the levels of both, pAKT and inducible NO synthase (iNOS). Furthermore, we observed that the expression of EPOR is associated with the expression of the mitochondrial marker VDAC1 in tissue arrays of lung cancer patients, suggesting that EPOR indeed helps to regulate mitochondrial biogenesis in tumors of cancer patients. Thus, our data imply that EPOR not only stimulates tumor growth but also regulates tumor metabolism and is a target for direct intervention against progression.
    Keywords:  OXPHOS; VDAC1; erythropoietin receptor; mitochondrial biogenesis; nitric oxide (NO); respirometry; tumor metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.976961
  29. Commun Biol. 2022 Aug 27. 5(1): 882
    Cancer cell histone density links global histone acetylation, mitochondrial proteome and histone acetylase inhibitor sensitivity.
    Christopher Bruhn, Giulia Bastianello, Marco Foiani.
      Chromatin metabolism is frequently altered in cancer cells and facilitates cancer development. While cancer cells produce large amounts of histones, the protein component of chromatin packaging, during replication, the potential impact of histone density on cancer biology has not been studied systematically. Here, we show that altered histone density affects global histone acetylation, histone deactylase inhibitor sensitivity and altered mitochondrial proteome composition. We present estimates of nuclear histone densities in 373 cancer cell lines, based on Cancer Cell Line Encyclopedia data, and we show that a known histone regulator, HMGB1, is linked to histone density aberrations in many cancer cell lines. We further identify an E3 ubiquitin ligase interactor, DCAF6, and a mitochondrial respiratory chain assembly factor, CHCHD4, as histone modulators. As systematic characterization of histone density aberrations in cancer cell lines, this study provides approaches and resources to investigate the impact of histone density on cancer biology.
    DOI:  https://doi.org/10.1038/s42003-022-03846-3
  30. Nat Neurosci. 2022 Aug 30.
    Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity.
    Minee L Choi, Alexandre Chappard, Bhanu P Singh, Catherine Maclachlan, Margarida Rodrigues, Evgeniya I Fedotova, Alexey V Berezhnov, Suman De, Christopher J Peddie, Dilan Athauda, Gurvir S Virdi, Weijia Zhang, James R Evans, Anna I Wernick, Zeinab Shadman Zanjani, Plamena R Angelova, Noemi Esteras, Andrey Y Vinokurov, Katie Morris, Kiani Jeacock, Laura Tosatto, Daniel Little, Paul Gissen, David J Clarke, Tilo Kunath, Lucy Collinson, David Klenerman, Andrey Y Abramov, Mathew H Horrocks, Sonia Gandhi.
      Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.
    DOI:  https://doi.org/10.1038/s41593-022-01140-3
  31. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2117396119
    Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.
    Na Ta, Chuanren Qu, Hao Wu, Di Zhang, Tiantian Sun, Yanjun Li, Jun Wang, Xiaohui Wang, Tieshan Tang, Quan Chen, Lei Liu.
      Ferroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in ferroptosis. However, how mitochondria sense the stress to activate ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochondrial glutathione transporter, to regulate mitoGSH levels. Specifically, knockdown of SLC25A11 in FUNDC2-knockout (KO) cells reduced mitoGSH and augmented erasin-induced ferroptosis. FUNDC2 also affected the stability of both SLC25A11 and glutathione peroxidase 4 (GPX4), key regulators for ferroptosis. Our results demonstrate that FUNDC2 modulates ferroptotic stress via regulating mitoGSH and further support a therapeutic strategy of cardioprotection by preventing mitoGSH depletion and ferroptosis.
    Keywords:  FUNDC2; SLC25A11; ferroptosis; mitoGSH; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2117396119
  32. Cell Metab. 2022 Aug 23. pii: S1550-4131(22)00348-5. [Epub ahead of print]
    PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis.
    Ju Youn Kim, Lily Q Wang, Valentina C Sladky, Tae Gyu Oh, Junlai Liu, Kaitlyn Trinh, Felix Eichin, Michael Downes, Mojgan Hosseini, Etienne D Jacotot, Ronald M Evans, Andreas Villunger, Michael Karin.
      Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.
    Keywords:  ER stress; IRE1; NAFLD; NASH; PIDDosome; SCAP; SREBP; caspase-2; steatohepatitis; steatosis
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.005
  33. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2119854119
    USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer.
    Haibiao Xie, Jin Zhou, Xijuan Liu, Yawei Xu, Austin J Hepperla, Jeremy M Simon, Tao Wang, Hongwei Yao, Chengheng Liao, Albert S Baldwin, Kan Gong, Qing Zhang.
      Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.
    Keywords:  USP13; ZHX2; ccRCC; deubiquitination
    DOI:  https://doi.org/10.1073/pnas.2119854119
  34. Mol Cell. 2022 Sep 01. pii: S1097-2765(22)00763-8. [Epub ahead of print]82(17): 3121-3123
    SLC4A7 and mTORC1 raise nucleotide synthesis with bicarbonate.
    Jessica C Koe, Keeley G Hewton, Seth J Parker.
      In this issue of Molecular Cell, Ali et al. (2022) show that bicarbonate uptake by SLC4A7 fuels de novo nucleotide synthesis and cell proliferation and is regulated by mTORC1.
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.010
  35. Biochim Biophys Acta Rev Cancer. 2022 Aug 27. pii: S0304-419X(22)00110-X. [Epub ahead of print]1877(5): 188785
    AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
    Vasudevarao Penugurti, Yasaswi Gayatri Mishra, Bramanandam Manavathi.
      Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188785
  36. Mol Nutr Food Res. 2022 Sep 01. e2200109
    Branched-chain amino acids and mitochondrial biogenesis: an overview and mechanistic summary.
    Jason S Hinkle, Caroline N Rivera, Roger A Vaughan.
      Branched-chain amino acids (BCAA) are essential in the diet and promote several vital cell responses which may have benefits for health and athletic performance, as well as disease prevention. While BCAA are well-known for their ability to stimulate muscle protein synthesis, their effects on cell energetics are also becoming well-documented, but these receive less attention. In this review, we highlight much of the current evidence demonstrating BCAA ability (as individual amino acids or as part of dietary mixtures) to alter regulators of cellular energetics with an emphasis on mitochondrial biogenesis and related signaling. Several studies have shown, both in vitro and in vivo, that BCAA (either individual or as a mixture) may promote signaling associated with increased mitochondrial biogenesis including the upregulation of master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as numerous downstream targets and related function. However, sparse data in humans and the difficulty of controlling variables associated with feeding studies leaves the physiological relevance of these findings unclear. Future well-controlled diet studies will be needed to assess if BCAA consumption is associated with increased mitochondrial biogenesis and improved metabolic outcomes in healthy and/or diseased human populations. This article is protected by copyright. All rights reserved.
    Keywords:  isoleucine; leucine; mitochondrial biogenesis; skeletal muscle; valine
    DOI:  https://doi.org/10.1002/mnfr.202200109
  37. Nat Commun. 2022 Aug 30. 13(1): 5089
    Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.
    L Orliaguet, T Ejlalmanesh, A Humbert, R Ballaire, M Diedisheim, J B Julla, D Chokr, J Cuenco, J Michieletto, J Charbit, D Lindén, J Boucher, C Potier, A Hamimi, S Lemoine, C Blugeon, P Legoix, S Lameiras, L G Baudrin, S Baulande, A Soprani, F A Castelli, F Fenaille, J P Riveline, E Dalmas, J Rieusset, J F Gautier, N Venteclef, F Alzaid.
      Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.
    DOI:  https://doi.org/10.1038/s41467-022-32813-z
  38. Front Cell Dev Biol. 2022 ;10 981464
    Editorial: Mitochondria as a hub in cellular signaling.
    Joshua S Stoolman, Anna Maria Porcelli, Inmaculada Martínez-Reyes.
      
    Keywords:  cancer; immunometabolism; mitochondria; neurodegeneration; redox; signaling
    DOI:  https://doi.org/10.3389/fcell.2022.981464
  39. Genome Biol. 2022 Sep 01. 23(1): 184
    MIRTH: Metabolite Imputation via Rank-Transformation and Harmonization.
    Benjamin A Freeman, Sophie Jaro, Tricia Park, Sam Keene, Wesley Tansey, Ed Reznik.
      Out of the thousands of metabolites in a given specimen, most metabolomics experiments measure only hundreds, with poor overlap across experimental platforms. Here, we describe Metabolite Imputation via Rank-Transformation and Harmonization (MIRTH), a method to impute unmeasured metabolite abundances by jointly modeling metabolite covariation across datasets which have heterogeneous coverage of metabolite features. MIRTH successfully recovers masked metabolite abundances both within single datasets and across multiple, independently-profiled datasets. MIRTH demonstrates that latent information about otherwise unmeasured metabolites is embedded within existing metabolomics data, and can be used to generate novel hypotheses and simplify existing metabolomic workflows.
    Keywords:  Imputation; Matrix factorization; Metabolomics; Missing data; Unmeasured metabolites
    DOI:  https://doi.org/10.1186/s13059-022-02738-3
  40. Elife. 2022 Sep 02. pii: e75908. [Epub ahead of print]11
    Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells.
    Nuria Vilaplana-Lopera, Vincent Cuminetti, Ruba Almaghrabi, Grigorios Papatzikas, Ashok Kumar Rout, Mark Jeeves, Elena González, Yara Alyahyawi, Alan Cunnigham, Ayşegüll Erdem, Frank Schnütgen, Manoj Raghavan, Sandeep Potluri, Jean-Baptiste Cazier, Jan Jacob Schuringa, Michelle A C Reed, Lorena Arranz, Ulrich Günther, Paloma Garcia.
      Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy.
    Keywords:  biochemistry; cancer biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.75908
  41. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2206327119
    Brain endothelial STING1 activation by Plasmodium-sequestered heme promotes cerebral malaria via type I IFN response.
    Teresa F Pais, Hajrabibi Ali, Joana Moreira da Silva, Nádia Duarte, Rita Neres, Chintan Chhatbar, Rita C Acúrcio, Rita C Guedes, Maria Carolina Strano Moraes, Bruno Costa-Silva, Ulrich Kalinke, Carlos Penha-Gonçalves.
      Cerebral malaria (CM) is a life-threatening form of Plasmodium falciparum infection caused by brain inflammation. Brain endothelium dysfunction is a hallmark of CM pathology, which is also associated with the activation of the type I interferon (IFN) inflammatory pathway. The molecular triggers and sensors eliciting brain type I IFN cellular responses during CM remain largely unknown. We herein identified the stimulator of interferon response cGAMP interactor 1 (STING1) as the key innate immune sensor that induces Ifnβ1 transcription in the brain of mice infected with Plasmodium berghei ANKA (Pba). This STING1/IFNβ-mediated response increases brain CXCL10 governing the extent of brain leukocyte infiltration and blood-brain barrier (BBB) breakdown, and determining CM lethality. The critical role of brain endothelial cells (BECs) in fueling type I IFN-driven brain inflammation was demonstrated in brain endothelial-specific IFNβ-reporter and STING1-deficient Pba-infected mice, which were significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from Pba-infected erythrocytes activated the STING1-dependent type I IFN response in BECs, a response requiring intracellular acidification. Fractionation of the EPs enabled us to identify a defined fraction carrying hemoglobin degradation remnants that activates STING1/IFNβ in the brain endothelium, a process correlated with heme content. Notably, stimulation of STING1-deficient BECs with heme, docking experiments, and in vitro binding assays unveiled that heme is a putative STING1 ligand. This work shows that heme resultant from the parasite heterotrophic activity operates as an alarmin, triggering brain endothelial inflammatory responses via the STING1/IFNβ/CXCL10 axis crucial to CM pathogenesis and lethality.
    Keywords:  CXCL10; IFN beta; STING1; brain endothelium; cerebral malaria
    DOI:  https://doi.org/10.1073/pnas.2206327119
  42. Mol Cell. 2022 Sep 01. pii: S1097-2765(22)00757-2. [Epub ahead of print]82(17): 3119-3121
    The Warburg effect: Saturation of mitochondrial NADH shuttles triggers aerobic lactate fermentation.
    Hyllana C D Medeiros, Sophia Y Lunt.
      In this issue of Molecular Cell, Wang et al. investigate the Warburg effect in proliferating cells and demonstrate that lactate fermentation is a secondary mechanism activated after mitochondrial shuttles exceed their capacity to oxidize cytosolic NADH.
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.004
  43. Nat Cell Biol. 2022 Sep 01.
    Identification of two pathways mediating protein targeting from ER to lipid droplets.
    Jiunn Song, Arda Mizrak, Chia-Wei Lee, Marcelo Cicconet, Zon Weng Lai, Wei-Chun Tang, Chieh-Han Lu, Stephanie E Mohr, Robert V Farese, Tobias C Walther.
      Pathways localizing proteins to their sites of action are essential for eukaryotic cell organization and function. Although mechanisms of protein targeting to many organelles have been defined, how proteins, such as metabolic enzymes, target from the endoplasmic reticulum (ER) to cellular lipid droplets (LDs) is poorly understood. Here we identify two distinct pathways for ER-to-LD protein targeting: early targeting at LD formation sites during formation, and late targeting to mature LDs after their formation. Using systematic, unbiased approaches in Drosophila cells, we identified specific membrane-fusion machinery, including regulators, a tether and SNARE proteins, that are required for the late targeting pathway. Components of this fusion machinery localize to LD-ER interfaces and organize at ER exit sites. We identified multiple cargoes for early and late ER-to-LD targeting pathways. Our findings provide a model for how proteins target to LDs from the ER either during LD formation or by protein-catalysed formation of membrane bridges.
    DOI:  https://doi.org/10.1038/s41556-022-00974-0
  44. Biochem Biophys Res Commun. 2022 Aug 18. pii: S0006-291X(22)01132-9. [Epub ahead of print]627 191-199
    The elevated D-2-hydroxyglutarate level found as a characteristic metabolic change of colon cancer in both in vitro and in vivo models.
    Esra Bulut Atalay, Hulya Ayar Kayali.
      The D-2-hydroxyglutarate (D-2-HG), whose normal cellular concentration is low, can be accumulated 10-100 times natural levels in some cancer types and participates in the carcinogenesis process. D-2-HG is produced by different pathways specific to cancer type. In this study, the level of significant metabolites produced in some metabolic pathways related to D-2-HG in the energy metabolism was determined in colon adenocarcinoma cell lines at different stages. Then, the differences in TCA and Cori cycle, glutaminolysis, and Glycolysis were investigated in the brain, colon, liver, and tumor tissues extracted from xenograft models. The levels of glucose, pyruvate, lactate, all TCA cycle intermediates, and D-2-HG were determined by the HPLC analysis, DNS method, and pyruvate assay. The intracellular D-2-HG level was found at 22.6 μmol/mg in primary (Caco-2) and 152.6 μmol/mg in metastatic (SW620) colon adenocarcinoma cells, whereas it could not be detected in colon epithelial cell line (CCD-18Co). In the xenograft models, D-2-HG could not be detected in CCD-18Co colon and brain tissues, whereas it was produced in Caco-2 and SW620 tissues. Most importantly, the level of D-2-HG was 7.4 and 19.9-fold increased in Caco-2 and SW620 tumor tissues compared to healthy tissue, respectively. In addition, the D-2-HG production pathways were investigated. The results revealed that the carbon source of D-2-HG is glucose, and the imbalance of wt-IDH1/2 enzymes plays a role in its production. Overall, the in vitro and in vivo results show that the enhanced production of endogenous D-2-HG is a characteristic change in the metabolism of colon cancer.
    Keywords:  2-Hydroxyglutarate; Colon cancer; Cori cycle; Metabolism; TCA cycle; wt-IDH1/2
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.019
  45. Mol Cell. 2022 Aug 25. pii: S1097-2765(22)00758-4. [Epub ahead of print]
    Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
    Andrew Murley, Kevin Wickham, Andrew Dillin.
      Cellular quiescence-reversible exit from the cell cycle-is an important feature of many cell types important for organismal health. Quiescent cells activate protective mechanisms that allow their persistence in the absence of growth and division for long periods of time. Aging and cellular dysfunction compromise the survival and re-activation of quiescent cells over time. Counteracting this decline are two interconnected organelles that lie at opposite ends of the secretory pathway: the endoplasmic reticulum and lysosomes. In this review, we highlight recent studies exploring the roles of these two organelles in quiescent cells from diverse contexts and speculate on potential other roles they may play, such as through organelle contact sites. Finally, we discuss emerging models of cellular quiescence, utilizing new cell culture systems and model organisms, that are suited to the mechanistic investigation of the functions of these organelles in quiescent cells.
    Keywords:  ER; aging; lysosome; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.005
  46. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2206708119
    Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.
    Lu Ren, Raghavender R Gopireddy, Guy Perkins, Hao Zhang, Valeriy Timofeyev, Yankun Lyu, Daphne A Diloretto, Pauline Trinh, Padmini Sirish, James L Overton, Wilson Xu, Nathan Grainger, Yang K Xiang, Elena N Dedkova, Xiao-Dong Zhang, Ebenezer N Yamoah, Manuel F Navedo, Phung N Thai, Nipavan Chiamvimonvat.
      The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 (Mfn2), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.
    Keywords:  bradycardia; heart failure; mitochondria; sinoatrial node; sinoatrial node dysfunction
    DOI:  https://doi.org/10.1073/pnas.2206708119
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