bims-camemi 2021-09-12 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2021–09–12
47 papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

A map of the altered glioma metabolism.
MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome.
Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.
T cells critically depend on pyruvate oxidation.
Metabolic requirements of NK cells during the acute response against retroviral infection.
In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium.
Role of Copper on Mitochondrial Function and Metabolism.
ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division.
Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.
Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.
The Mitochondrial Ca2+ Uniporter is a Central Regulator of Interorganellar Ca2+ Transfer and NFAT Activation.
Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges.
The immunometabolite itaconate inhibits heme synthesis and remodels cellular metabolism in erythroid precursors.
A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation.
The versatility of plant organic acid metabolism in leaves is underpinned by mitochondrial malate-citrate exchange.
Lipids modulate the BH3-independent membrane targeting and activation of BAX and Bcl-xL.
Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer.
The yeast mitochondrial succinylome: Implications for regulation of mitochondrial nucleoids.
Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis.
The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.
Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.
Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.
Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPβ transgenic mice.
Adipocyte heterogeneity revealed by spatial transcriptomics of human adipose tissue: Painting and more.
Cellular Interactome of Mitochondrial Voltage-Dependent Anion Channels: Oligomerization and Channel (Mis)Regulation.
Genomic instability and metabolism in cancer.
Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression.
Mitochondrial DNA: Unraveling the "other" genome.
The MYC oncogene - the grand orchestrator of cancer growth and immune evasion.
Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.
β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.
Three dimensions of autophagy in regulating tumor growth: Cell survival/death, cell proliferation, and tumor dormancy.
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.
Revisiting energy expenditure: how to correct mouse metabolic rate for body mass.
Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.
MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex.
Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2.
An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer.
Trapped topoisomerase-DNA covalent complexes in the mitochondria and their role in human diseases.
Mitochondrial Dynamics in Drug-Induced Liver Injury.
Glutathione is an aging-related metabolic signature in the mouse kidney.
Tilting MYC toward cancer cell death.
The nexus between redox state and intermediary metabolism.
MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.
NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.
Microbiome and cancer.
Exosomes as mediators of intercellular crosstalk in metabolism.

Trends Mol Med. 2021 Sep 03. pii: S1471-4914(21)00196-9. [Epub ahead of print]

A map of the altered glioma metabolism.

Ruhi Deshmukh, Maria Francesca Allega, Saverio Tardito.

  The frequent occurrence of neomorphic isocitrate dehydrogenase 1 (IDH1) mutations in low-grade glioma led to an IDH-centric classification of these tumors. However, exploiting metabolic alterations of glioma for diagnostic imaging and treatment has marginally improved patients' prognosis. Here we discuss the nutritional microenvironment of glioma, shaped by the distinctive dependence of the brain on glucose and ketone bodies for energy, and on amino acids for neurotransmission. We highlight the progress in metabolic applications for glioma diagnosis and therapy, and present a map that streamlines the rewired glioma metabolism. The map illustrates the altered reactions in central carbon and nitrogen metabolism that drive glioma biology, and represent metabolic vulnerabilities with translational potential.

Keywords:  IDH1 mutation; cancer metabolism; glioblastoma; glioma

DOI:  https://doi.org/10.1016/j.molmed.2021.07.011
Hum Mol Genet. 2021 Sep 07. pii: ddab254. [Epub ahead of print]

MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome.

Sagnika Ghosh, Mohammad Zulkifli, Alaumy Joshi, Manigandan Venkatesan, Allen Cristel, Neelanjan Vishnu, Muniswamy Madesh, Vishal M Gohil.

Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.

DOI: https://doi.org/10.1093/hmg/ddab254
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2025932118. [Epub ahead of print]118(37):

Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.

Joshua C Drake, Rebecca J Wilson, Rhianna C Laker, Yuntian Guan, Hannah R Spaulding, Anna S Nichenko, Wenqing Shen, Huayu Shang, Maya V Dorn, Kian Huang, Mei Zhang, Aloka B Bandara, Matthew H Brisendine, Jennifer A Kashatus, Poonam R Sharma, Alexander Young, Jitendra Gautam, Ruofan Cao, Horst Wallrabe, Paul A Chang, Michael Wong, Eric M Desjardins, Simon A Hawley, George J Christ, David F Kashatus, Clint L Miller, Matthew J Wolf, Ammasi Periasamy, Gregory R Steinberg, D Grahame Hardie, Zhen Yan.

  Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5' AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

Keywords:  AMPK; exercise; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2025932118
Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00373-9. [Epub ahead of print]33(9): 1719-1720

T cells critically depend on pyruvate oxidation.

Christopher Schrecker, Andrew M Intlekofer.

Supporting the notion that cell lineage is a key determinant of cancer cell metabolism, Jun et al. (2021) identify a selective requirement for pyruvate dehydrogenase (PDH) activity in T cells and T cell leukemia, but not hematopoietic stem cells (HSCs) or myeloid leukemia, in this issue of Cell Metabolism.

DOI: https://doi.org/10.1016/j.cmet.2021.08.010
Nat Commun. 2021 Sep 10. 12(1): 5376

Metabolic requirements of NK cells during the acute response against retroviral infection.

Elisabeth Littwitz-Salomon, Diana Moreira, Joe N Frost, Chloe Choi, Kevin T Liou, David K Ahern, Simon O'Shaughnessy, Bernd Wagner, Christine A Biron, Hal Drakesmith, Ulf Dittmer, David K Finlay.

Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.

DOI: https://doi.org/10.1038/s41467-021-25715-z
J Mol Cell Cardiol. 2021 Sep 03. pii: S0022-2828(21)00172-3. [Epub ahead of print]

In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium.

Kyle L Fulghum, Timothy N Audam, Pawel K Lorkiewicz, Yuting Zheng, Michael Merchant, Timothy D Cummins, William L Dean, Teresa A Cassel, Teresa W M Fan, Bradford G Hill.

  Glucose metabolism comprises numerous amphibolic metabolites that provide precursors for not only the synthesis of cellular building blocks but also for ATP production. In this study, we tested how phosphofructokinase-1 (PFK1) activity controls the fate of glucose-derived carbon in murine hearts in vivo. PFK1 activity was regulated by cardiac-specific overexpression of kinase- or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgenes in mice (termed GlycoLo or GlycoHi mice, respectively). Dietary delivery of 13C6-glucose to these mice, followed by deep network metabolic tracing, revealed that low rates of PFK1 activity promote selective routing of glucose-derived carbon to the purine synthesis pathway to form 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Consistent with a mechanism of physical channeling, we found multimeric protein complexes that contained phosphoribosylaminoimidazole carboxylase (PAICS)-an enzyme important for AICAR biosynthesis, as well as chaperone proteins such as Hsp90 and other metabolic enzymes. We also observed that PFK1 influenced glucose-derived carbon deposition in glycogen, but did not affect hexosamine biosynthetic pathway activity. These studies demonstrate the utility of deep network tracing to identify metabolic channeling and changes in biosynthetic pathway activity in the heart in vivo and present new potential mechanisms by which metabolic branchpoint reactions modulate biosynthetic pathways.

Keywords:  Anabolism; Channeling; Glycolysis; Metabolomics; Metabolons; Stable isotope

DOI:  https://doi.org/10.1016/j.yjmcc.2021.08.013
Front Mol Biosci. 2021 ;8 711227

Role of Copper on Mitochondrial Function and Metabolism.

Lina M Ruiz, Allan Libedinsky, Alvaro A Elorza.

  Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.

Keywords:  ROS; cancer; copper; differentiation; hematopoietic stem cells (HSCs); metabolic reprograming; mitochondria; proliferation

DOI:  https://doi.org/10.3389/fmolb.2021.711227
Nat Commun. 2021 Sep 09. 12(1): 5354

ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division.

Maxime Boutry, Peter K Kim.

Mitochondrial division is not an autonomous event but involves multiple organelles, including the endoplasmic reticulum (ER) and lysosomes. Whereas the ER drives the constriction of mitochondrial membranes, the role of lysosomes in mitochondrial division is not known. Here, using super-resolution live-cell imaging, we investigate the recruitment of lysosomes to the site of mitochondrial division. We find that the ER recruits lysosomes to the site of division through the interaction of VAMP-associated proteins (VAPs) with the lysosomal lipid transfer protein ORP1L to induce a three-way contact between the ER, lysosome, and the mitochondrion. We also show that ORP1L might transport phosphatidylinositol-4-phosphate (PI(4)P) from lysosomes to mitochondria, as inhibiting its transfer or depleting PI(4)P at the mitochondrial division site impairs fission, demonstrating a direct role for PI(4)P in the division process. Our findings support a model where the ER recruits lysosomes to act in concert at the fission site for the efficient division of mitochondria.

DOI: https://doi.org/10.1038/s41467-021-25621-4
J Cereb Blood Flow Metab. 2021 Sep 08. 271678X211042112

Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

Abdelhakim Khellaf, Nuria Marco Garcia, Tamara Tajsic, Aftab Alam, Matthew G Stovell, Monica J Killen, Duncan J Howe, Mathew R Guilfoyle, Ibrahim Jalloh, Ivan Timofeev, Michael P Murphy, T Adrian Carpenter, David K Menon, Ari Ercole, Peter J Hutchinson, Keri Lh Carpenter, Eric P Thelin, Adel Helmy.

  Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.

Keywords:  Cerebral metabolism; microdialysis; mitochondrial dysfunction; succinate; traumatic brain injury (Human)

DOI:  https://doi.org/10.1177/0271678X211042112
Front Mol Biosci. 2021 ;8 706650

Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.

Caterina Bartolacci, Cristina Andreani, Yasmin El-Gammal, Pier Paolo Scaglioni.

  HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.

Keywords:  RAS oncogenes; ferroptosis; lipid metabolism; oxidative stress; tumorigenesis

DOI:  https://doi.org/10.3389/fmolb.2021.706650
J Biol Chem. 2021 Sep 06. pii: S0021-9258(21)00976-5. [Epub ahead of print] 101174

The Mitochondrial Ca2+ Uniporter is a Central Regulator of Interorganellar Ca2+ Transfer and NFAT Activation.

Ryan E Yoast, Scott M Emrich, Xuexin Zhang, Ping Xin, Vikas Arige, Trayambak Pathak, J Cory Benson, Martin T Johnson, Ahmed Emam Abdelnaby, Natalia Lakomski, Nadine Hempel, Jung Min Han, Geneviève Dupont, David I Yule, James Sneyd, Mohamed Trebak.

  Mitochondrial Ca2+ uptake tailors the strength of stimulation of plasma membrane phospholipase C-coupled receptors to that of cellular bioenergetics. However, how Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) shapes receptor-evoked inter-organellar Ca2+ signaling is unknown. Here, we used CRISPR/Cas9 gene knockout, sub-cellular Ca2+ imaging and mathematical modeling to show that MCU is a universal regulator of intracellular Ca2+ signaling across mammalian cell types. MCU activity sustains cytosolic Ca2+ signaling by preventing Ca2+-dependent inactivation (CDI) of store-operated Ca2+ release-activated Ca2+ (CRAC) channels and by inhibiting Ca2+ extrusion. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca2+ responses to store depletion. Physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca2+ oscillations, endoplasmic reticulum (ER) Ca2+ refilling, nuclear translocation of nuclear factor for activated T-cells (NFAT) transcription factors, and cell proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Our data show that MCU has dual counterbalancing functions at the cytosol-mitochondria interface, whereby the cell-specific MCU-dependent cytosolic Ca2+ clearance and buffering capacity of mitochondria reciprocally regulate inter-organellar Ca2+ transfer and NFAT nuclear translocation during receptor-evoked signaling. These findings highlight the critical dual function of the MCU not only in the acute Ca2+ buffering by mitochondria but also in shaping ER and cytosolic Ca2+ signals that regulate cellular transcription and function.

Keywords:  CRAC channels; MCU; NFAT; SOCE; calcium oscillations; calcium signaling; mitochondria

DOI:  https://doi.org/10.1016/j.jbc.2021.101174
Annu Rev Pharmacol Toxicol. 2021 Sep 09.

Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges.

Laura Torrente, Gina M DeNicola.

The transcription factor NRF2 coordinates the expression of a vast array of cytoprotective and metabolic genes in response to various stress inputs to restore cellular homeostasis. Transient activation of NRF2 in healthy tissues has been long recognized as a cellular defense mechanism and is critical to prevent cancer initiation by carcinogens. However, cancer cells frequently hijack the protective capability of NRF2 to sustain the redox balance and meet their metabolic requirements for proliferation. Further, aberrant activation of NRF2 in cancer cells confers resistance to commonly used chemotherapeutic agents and radiotherapy. During the last decade, many research groups have attempted to block NRF2 activity in tumors to counteract the survival and proliferative advantage of cancer cells and reverse resistance to treatment. In this review, we highlight the role of NRF2 in cancer progression and discuss the past and current approaches to disable NRF2 signaling in tumors. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pharmtox-052220-104025
Blood Adv. 2021 Sep 07. pii: bloodadvances.2021004750. [Epub ahead of print]

The immunometabolite itaconate inhibits heme synthesis and remodels cellular metabolism in erythroid precursors.

Jason R Marcero, James Eric Cox, Hector A Bergonia, Amy E Medlock, John D Phillips, Harry A Dailey.

As part of the inflammatory response by macrophages, Irg1 is induced resulting in millimolar quantities of itaconate being produced. This immunometabolite remodels the macrophage metabolome and acts as an antimicrobial agent when excreted. Itaconate is not synthesized within the erythron, but instead may be acquired from central macrophages within the erythroid island. Previously we reported that itaconate inhibits hemoglobinzation of developing erythroid cells. Herein we demonstrate that this is accomplished by inhibition of tetrapyrrole synthesis. In differentiating erythroid precursors, cellular heme and protoporphyrin IX synthesis are reduced by itaconate at an early step in the pathway. In addition, itaconate causes global alterations in cellular metabolite pools resulting in elevated levels of succinate, 2-hydroxyglutarate, pyruvate, glyoxylate, and intermediates of glycolytic shunts. Itaconate taken up by the developing erythron can be converted to itaconyl-CoA by the enzyme succinyl-CoA:glutarate-CoA transferase. Propionyl-CoA, propionyl-carnitine, methylmalonic acid, heptadecanoic acid and nonanoic acid, as well as the aliphatic amino acids threonine, valine, methionine, and isoleucine are increased, likely due to the impact of endogenous itaconyl-CoA synthesis. We further show that itaconyl-CoA is a competitive inhibitor of the erythroid-specific 5-aminolevulinate synthase (ALAS2), the first and rate-limiting step in heme synthesis. These findings strongly support our hypothesis that the inhibition of heme synthesis observed in chronic inflammation is mediated not only by iron limitation, but also by limitation of tetrapyrrole synthesis at the point of ALAS2 catalysis by itaconate. Thus, we propose that macrophage-derived itaconate promotes anemia during an inflammatory response in the erythroid compartment.

DOI: https://doi.org/10.1182/bloodadvances.2021004750
Nat Metab. 2021 Sep 09.

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation.

Li Li, Devon M Conradson, Vinita Bharat, Min Joo Kim, Chung-Han Hsieh, Paras S Minhas, Amanda M Papakyrikos, Aarooran Sivakumaran Durairaj, Anthony Ludlam, Katrin I Andreasson, Linda Partridge, Michael A Cianfrocco, Xinnan Wang.

Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60-Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson's disease and Friedreich's ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

DOI: https://doi.org/10.1038/s42255-021-00443-2
Plant Cell. 2021 Sep 08. pii: koab223. [Epub ahead of print]

The versatility of plant organic acid metabolism in leaves is underpinned by mitochondrial malate-citrate exchange.

Chun Pong Lee, Marlene Elsässer, Philippe Fuchs, Ricarda Fenske, Markus Schwarzländer, A Harvey Millar.

Malate and citrate underpin the characteristic flexibility of central plant metabolism by linking mitochondrial respiratory metabolism with cytosolic biosynthetic pathways. However, the identity of mitochondrial carrier proteins that influence both processes has remained elusive. Here we show by a systems approach that DICARBOXYLATE CARRIER 2 (DIC2) facilitates mitochondrial malate-citrate exchange in vivo in Arabidopsis thaliana. DIC2 knockout (dic2-1) retards growth of vegetative tissues. In vitro and in organello analyses demonstrate that DIC2 preferentially imports malate against citrate export, which is consistent with altered malate and citrate utilisation in response to prolonged darkness of dic2-1 plants or a sudden shift to darkness of dic2-1 leaves. Furthermore, isotopic glucose tracing reveals a reduced flux towards citrate in dic2-1, which results in a metabolic diversion towards amino acid synthesis. These observations reveal the physiological function of DIC2 in mediating the flow of malate and citrate between the mitochondrial matrix and other cell compartments.

DOI: https://doi.org/10.1093/plcell/koab223
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2025834118. [Epub ahead of print]118(37):

Lipids modulate the BH3-independent membrane targeting and activation of BAX and Bcl-xL.

Victor Vasquez-Montes, Mykola V Rodnin, Alexander Kyrychenko, Alexey S Ladokhin.

  Regulation of apoptosis is tightly linked with the targeting of numerous Bcl-2 proteins to the mitochondrial outer membrane (MOM), where their activation or inhibition dictates cell death or survival. According to the traditional view of apoptotic regulation, BH3-effector proteins are indispensable for the cytosol-to-MOM targeting and activation of proapoptotic and antiapoptotic members of the Bcl-2 protein family. This view is challenged by recent studies showing that these processes can occur in cells lacking BH3 effectors by as yet to be determined mechanism(s). Here, we exploit a model membrane system that recapitulates key features of MOM to demonstrate that the proapoptotic Bcl-2 protein BAX and antiapoptotic Bcl-xL have an inherent ability to interact with membranes in the absence of BH3 effectors, but only in the presence of cellular concentrations of Mg2+/Ca2+ Under these conditions, BAX and Bcl-xL are selectively targeted to membranes, refolded, and activated in the presence of anionic lipids especially the mitochondrial-specific lipid cardiolipin. These results provide a mechanistic explanation for the mitochondrial targeting and activation of Bcl-2 proteins in cells lacking BH3 effectors. At cytosolic Mg2+ levels, the BH3-independent activation of BAX could provide localized amplification of apoptotic signaling at regions enriched in cardiolipin (e.g., contact sites between MOM and mitochondrial inner membrane). Increases in MOM cardiolipin, as well as cytosolic [Ca2+] during apoptosis could further contribute to its MOM targeting and activity. Meanwhile, the BH3-independent targeting and activation of Bcl-xL to the MOM is expected to counter the action of proapoptotic BAX, thereby preventing premature commitment to apoptosis.

Keywords:  apoptosis; divalent cations; membrane protein folding; mitochondria permeabilization; protein–lipid interactions

DOI:  https://doi.org/10.1073/pnas.2025834118
Nat Commun. 2021 Sep 07. 12(1): 5321

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer.

Jianhuang Lin, Heng Liu, Takeshi Fukumoto, Joseph Zundell, Qingqing Yan, Chih-Hang Anthony Tang, Shuai Wu, Wei Zhou, Dajiang Guo, Sergey Karakashev, Chih-Chi Andrew Hu, Kavitha Sarma, Andrew V Kossenkov, Rugang Zhang.

CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

DOI: https://doi.org/10.1038/s41467-021-25684-3
J Biol Chem. 2021 Sep 01. pii: S0021-9258(21)00957-1. [Epub ahead of print] 101155

The yeast mitochondrial succinylome: Implications for regulation of mitochondrial nucleoids.

Jan Frankovsky, Barbora Keresztesová, Jana Bellová, Nina Kunová, Nikola Čanigová, Katerina Hanakova, Jacob A Bauer, Gabriela Ondrovičová, Veronika Lukáčová, Barbara Siváková, Zbynek Zdrahal, Vladimír Pevala, Katarína Procházková, Jozef Nosek, Peter Baráth, Eva Kutejova, Lubomir Tomaska.

  Acylation modifications, such as the succinylation of lysine, are post-translational modifications and a powerful means of regulating protein activity. Some acylations occur nonenzymatically, driven by an increase in the concentration of acyl group donors. Lysine succinylation has a profound effect on the corresponding site within the protein, as it dramatically changes the charge of the residue. In eukaryotes, it predominantly affects mitochondrial proteins because the donor of succinate, succinyl-coenzyme A, is primarily generated in the tricarboxylic acid (TCA) cycle. Although numerous succinylated mitochondrial proteins have been identified in Saccharomyces cerevisiae, a more detailed characterization of the yeast mitochondrial succinylome is still lacking. Here we performed a proteomic mass spectrometry analysis of purified yeast mitochondria and detected 314 succinylated mitochondrial proteins with 1763 novel succinylation sites. The mitochondrial nucleoid, a complex of mitochondrial DNA (mtDNA) and mitochondrial proteins, is one of the structures whose protein components are affected by succinylation. We found that Abf2p, the principal component of mt-nucleoids responsible for compacting mtDNA in S. cerevisiae, can be succinylated in vivo on at least thirteen lysine residues. Abf2p succinylation in vitro inhibits its DNA-binding activity and reduces its sensitivity to digestion by the ATP-dependent ScLon protease. We conclude that changes in the metabolic state of a cell resulting in an increase in concentration of TCA intermediates may affect mitochondrial functions.

Keywords:  DNA-protein interaction; lysine succinylation; mitochondria; mitochondrial DNA; mitochondrial nucleoid; post-translational modification (PTM); proteomics; succinylome; yeast

DOI:  https://doi.org/10.1016/j.jbc.2021.101155
Nature. 2021 Sep 08.

Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis.

Roarke A Kamber, Yoko Nishiga, Bhek Morton, Allison M Banuelos, Amira A Barkal, Felipe Vences-Catalán, Mingxin Gu, Daniel Fernandez, Jose A Seoane, David Yao, Katherine Liu, Sijie Lin, Kaitlyn Spees, Christina Curtis, Livnat Jerby-Arnon, Irving L Weissman, Julien Sage, Michael C Bassik.

Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells1-7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

DOI: https://doi.org/10.1038/s41586-021-03879-4
Autophagy. 2021 Sep 05. 1-3

The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.

Yumiko Oshima, Nicolas Verhoeven, Etienne Cartier, Mariusz Karbowski.

  Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution". Formation of mosaic mitochondria requires mitochondrial fission and active mitochondrial translation. In cell lines deficient in PRKN activity, this process is followed by severing the outer mitochondrial membrane (OMM) and ubiquitination of the inner mitochondrial membrane (IMM) proteins (including TRAP1 and CPOX), recruitment of autophagy receptors, and formation of mito-autophagosomes. In contrast, in PRKN-expressing cells, mitochondria with high CYCS and CPOX levels are preferentially targeted by PRKN, leading to OMM ubiquitination and canonical PRKN-PINK1-mediated autophagy.

Keywords:  DRP1; Parkin; mitochondria; mitochondrial translation; mitophagy; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2021.1964887
Neuromolecular Med. 2021 Sep 06.

Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.

Zhihao Wu, Winson S Ho, Rongze Lu.

  As a multi-functional cellular organelle, mitochondrial metabolic reprogramming is well recognized as a hallmark of cancer. The center of mitochondrial metabolism is oxidative phosphorylation (OXPHOS), in which cells use enzymes to oxidize nutrients, thereby converting the chemical energy to the biological energy currency ATPs. OXPHOS also creates the mitochondrial membrane potential and serve as the driving force of other mitochondrial metabolic pathways and experiences significant reshape in the different stages of tumor progression. In this minireview, we reviewed the major mitochondrial pathways that are connected to OXPHOS and are affected in cancer cells. In addition, we summarized the function of novel bio-active molecules targeting mitochondrial metabolic processes such as OXPHOS, mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising antitumor candidates in recent studies.

Keywords:  Glioblastoma; Mitochondrial dysfunction; OXPHOS inhibitors

DOI:  https://doi.org/10.1007/s12017-021-08678-8
Aging Cell. 2021 Sep 09. e13472

Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.

Kerry C Ryan, Zahra Ashkavand, Shaarika Sarasija, Jocelyn T Laboy, Rohan Samarakoon, Kenneth R Norman.

  Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.

Keywords:   Caenorhabditis elegans ; Alzheimer; aging; calcium; mTORC1; mitochondria; presenilin

DOI:  https://doi.org/10.1111/acel.13472
Mol Psychiatry. 2021 Sep 06.

Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPβ transgenic mice.

Eun Hee Ahn, Kecheng Lei, Seong Su Kang, Zhi-Hao Wang, Xia Liu, Wei Hong, Yu Tian Wang, Laura E Edgington-Mitchell, Lingjing Jin, Keqiang Ye.

Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBPβ transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBPβ/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPβ mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBPβ mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPβ/AEP pathway.

DOI: https://doi.org/10.1038/s41380-021-01284-x
Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00374-0. [Epub ahead of print]33(9): 1721-1722

Adipocyte heterogeneity revealed by spatial transcriptomics of human adipose tissue: Painting and more.

Dominique Langin.

Adipose tissue is composed of adipocytes and cells from the stromal vascular fraction. In this issue of Cell Metabolism, Bäckdahl et al. (2021) use spatial transcriptomics to provide a first glimpse at the architecture of human adipose tissue. The authors identify distinct adipocyte subpopulations with specific metabolic features.

DOI: https://doi.org/10.1016/j.cmet.2021.08.011
ACS Chem Neurosci. 2021 Sep 09.

Cellular Interactome of Mitochondrial Voltage-Dependent Anion Channels: Oligomerization and Channel (Mis)Regulation.

Altmash Khan, Gifty Kuriachan, Radhakrishnan Mahalakshmi.

  Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane are known conventionally as metabolite flux proteins. However, research findings in the past decade have revealed the multifaceted regulatory roles of VDACs, from governing cellular physiology and mitochondria-mediated apoptosis to directly regulating debilitating cancers and neurodegenerative diseases. VDACs achieve these diverse functions by establishing isoform-dependent stereospecific interactomes in the cell with the cytosolic constituents and endoplasmic reticulum complexes, and the machinery of the mitochondrial compartments. VDACs are now increasingly recognized as regulatory hubs of the cell. Not surprisingly, even the transient misregulation of VDACs results directly in mitochondrial dysfunction. Additionally, human VDACs are now implicated in interaction with aggregation-prone cytosolic proteins, including Aβ, tau, and α-synuclein, contributing directly to the onset of Alzheimer's and Parkinson's diseases. Deducing the interaction dynamics and mechanisms can lead to VDAC-targeted peptide-based therapeutics that can alleviate neurodegenerative states. This review succinctly presents the latest findings of the VDAC interactome, and the mode(s) of VDAC-dependent regulation of biochemical physiology. We also discuss the relevance of VDACs in pathophysiological states and aggregation-associated diseases and address how VDACs will facilitate the development of next-generation precision medicines.

Keywords:  VDAC; human mitochondrial protein; interaction network; membrane channel; mitochondrial diseases; neurodegeneration; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.1c00429
Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00063-0. [Epub ahead of print]364 241-265

Genomic instability and metabolism in cancer.

Haojian Li, Susan E Zimmerman, Urbain Weyemi.

  Genomic instability and metabolic reprogramming are among the key hallmarks discriminating cancer cells from normal cells. The two phenomena contribute to the robust and evasive nature of cancer, particularly when cancer cells are exposed to chemotherapeutic agents. Genomic instability is defined as the increased frequency of mutations within the genome, while metabolic reprogramming is the alteration of metabolic pathways that cancer cells undergo to adapt to increased bioenergetic demand. An underlying source of these mutations is the aggregate product of damage to the DNA, and a defective repair pathway, both resulting in the expansion of genomic lesions prior to uncontrolled proliferation and survival of cancer cells. Exploitation of DNA damage and the subsequent DNA damage response (DDR) have aided in defining therapeutic approaches in cancer. Studies have demonstrated that targeting metabolic reprograming yields increased sensitivity to chemo- and radiotherapies. In the past decade, it has been shown that these two key features are interrelated. Metabolism impacts DNA damage and DDR via regulation of metabolite pools. Conversely, DDR affects the response of metabolic pathways to therapeutic agents. Because of the interplay between genomic instability and metabolic reprogramming, we have compiled findings which more selectively highlight the dialog between metabolism and DDR, with a particular focus on glucose metabolism and double-strand break (DSB) repair pathways. Decoding this dialog will provide significant clues for developing combination cancer therapies.

Keywords:  Cancer; DNA repair; Genomic instability; Glycolysis; Metabolism; Mitochondrial homeostasis

DOI:  https://doi.org/10.1016/bs.ircmb.2021.05.004
Cancers (Basel). 2021 Sep 04. pii: 4457. [Epub ahead of print]13(17):

Kv1.3 Controls Mitochondrial Dynamics during Cell Cycle Progression.

Jesusa Capera, Mireia Pérez-Verdaguer, María Navarro-Pérez, Antonio Felipe.

  The voltage-gated potassium channel Kv1.3 is a potential therapeutic target for obesity and diabetes. The genetic ablation and pharmacological inhibition of Kv1.3 lead to a lean phenotype in rodents. The mechanism of regulation of body weight and energy homeostasis involves Kv1.3 expression in different organs, including white and brown adipose tissues. Here, we show that Kv1.3 promotes the proliferation of preadipocytes through the control of mitochondrial dynamics. Kv1.3 is expressed in mitochondria exhibiting high affinity for the perinuclear population. The mitochondrial network is highly dynamic during the cell cycle, showing continuous fusion-fission events. The formation of a hyperfused mitochondrial network at the G1/S phase of the cell cycle is dependent on Kv1.3 expression. Our results demonstrate that Kv1.3 promotes preadipocyte proliferation and differentiation by controlling mitochondrial membrane potential and mitochondrial dynamics at the G1 phase of the cell cycle.

Keywords:  adipocytes; fusion/fission; mitochondria; potassium channels; proliferation

DOI:  https://doi.org/10.3390/cancers13174457
J Am Assoc Nurse Pract. 2021 Sep 01. 33(9): 673-675

Mitochondrial DNA: Unraveling the "other" genome.

Beth Heuer.

ABSTRACT: The mitochondrial genome, which contains all of the hereditary information within human mitochondria, consists of 16,569 base pairs of double-stranded DNA that encode 37 genes. Pathogenic mutations of mitochondrial DNA (mtDNA) cause dysfunction of the respiratory chain and the process of oxidative phosphorylation (OXPHOS), leading to impaired adenosine triphosphate synthesis. Nuclear DNA (nDNA) mutations can affect structural subunits or assembly factors of one of the five OXPHOS complexes. Mitochondrial diseases are a heterogeneous group of disorders, ranging from mtDNA single-point mutations and large-scale deletions to mitochondrial depletion syndromes, resulting from nDNA pathogenic mutations. Manifestations of mitochondrial disease are multisystemic, and organs with substantial energy requirements are most typically affected. Mitochondrial disorders are progressive in nature, and prognosis is dependent on the organs involved and the rate and severity of disease progression. A multidisciplinary team approach is needed to monitor and manage disease sequelae.

DOI: https://doi.org/10.1097/JXX.0000000000000646
Nat Rev Clin Oncol. 2021 Sep 10.

The MYC oncogene - the grand orchestrator of cancer growth and immune evasion.

Renumathy Dhanasekaran, Anja Deutzmann, Wadie D Mahauad-Fernandez, Aida S Hansen, Arvin M Gouw, Dean W Felsher.

The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.

DOI: https://doi.org/10.1038/s41571-021-00549-2
Nat Commun. 2021 Sep 09. 12(1): 5248

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

Hema Adhikari, Walaa E Kattan, Shivesh Kumar, Pei Zhou, John F Hancock, Christopher M Counter.

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.

DOI: https://doi.org/10.1038/s41467-021-25523-5
Elife. 2021 09 07. pii: e71270. [Epub ahead of print]10

β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.

Ross T Lindsay, Sophie Dieckmann, Dominika Krzyzanska, Dominic Manetta-Jones, James A West, Cecilia Castro, Julian L Griffin, Andrew J Murray.

  Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.

Keywords:  Heart; Ischaemia; Langendorff; biochemistry; cardiomyocyte; cell biology; chemical biology; rat

DOI:  https://doi.org/10.7554/eLife.71270
Biochim Biophys Acta Mol Basis Dis. 2021 Sep 03. pii: S0925-4439(21)00198-8. [Epub ahead of print] 166265

Three dimensions of autophagy in regulating tumor growth: Cell survival/death, cell proliferation, and tumor dormancy.

Yongqiang Chen, Spencer B Gibson.

  Autophagy is an intracellular lysosomal degradation process involved in multiple facets of cancer biology. Various dimensions of autophagy are associated with tumor growth and cancer progression, and here we focus on the dimensions involved in regulation of cell survival/cell death, cell proliferation and tumor dormancy. The first dimension of autophagy supports cell survival under stress within tumors and under certain contexts drives cell death, impacting tumor growth. The second dimension of autophagy promotes proliferation through directly regulating cell cycle or indirectly maintaining metabolism, increasing tumor growth. The third dimension of autophagy facilitates tumor cell dormancy, contributing to cancer treatment resistance and cancer recurrence. The intricate relationship between these three dimensions of autophagy influences the extent of tumor growth and cancer progression. In this review, we summarize the roles of the three dimensions of autophagy in tumor growth and cancer progression, and discuss unanswered questions in these fields.

Keywords:  Autophagy; Cell death; Cell survival; Proliferation; Tumor dormacy; Tumor growth

DOI:  https://doi.org/10.1016/j.bbadis.2021.166265
Hum Mol Genet. 2021 Sep 11. pii: ddab257. [Epub ahead of print]

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.

Wen-Qiang Zheng, Signe Vandal Pedersen, Kyle Thompson, Emanuele Bellacchio, Courtney E French, Benjamin Munro, Toni S Pearson, Julie Vogt, Daria Diodato, Tue Diemer, Anja Ernst, Rita Horvath, Manali Chitre, Jakob Ek, Flemming Wibrand, Dorothy K Grange, Lucy Raymond, Xiao-Long Zhou, Robert W Taylor, Elsebet Ostergaard.

TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Additionally, we document seven novel TARS2 variants-one nonsense variant and six missense variants-that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modelling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

DOI: https://doi.org/10.1093/hmg/ddab257
Nat Metab. 2021 Sep 06.

Revisiting energy expenditure: how to correct mouse metabolic rate for body mass.

Timo D Müller, Martin Klingenspor, Matthias H Tschöp.

DOI: https://doi.org/10.1038/s42255-021-00451-2
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2104093118. [Epub ahead of print]118(37):

Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.

Rachel-Ann A Garibsingh, Elias Ndaru, Alisa A Garaeva, Yueyue Shi, Laura Zielewicz, Paul Zakrepine, Massimiliano Bonomi, Dirk J Slotboom, Cristina Paulino, Christof Grewer, Avner Schlessinger.

  ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here, we rationally designed stereospecific inhibitors exploiting specific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final structures combined with molecular dynamics simulations reveal multiple pharmacologically relevant conformations in the ASCT2 binding site as well as a previously unknown mechanism of stereospecific inhibition. Furthermore, this integrated analysis guided the design of a series of unique ASCT2 inhibitors. Our results provide a framework for future development of cancer therapeutics targeting nutrient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery.

Keywords:  MD simulations; cryo-EM; homology modeling; membrane protein; solute carrier transporter

DOI:  https://doi.org/10.1073/pnas.2104093118
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2024824118. [Epub ahead of print]118(37):

MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex.

Paula Llabata, Manuel Torres-Diz, Antonio Gomez, Laureano Tomas-Daza, Octavio A Romero, Joaquim Grego-Bessa, Pere Llinas-Arias, Alfonso Valencia, Manel Esteller, Biola M Javierre, Xiaoyang Zhang, Montse Sanchez-Cespedes.

  The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.

Keywords:  MAX; MGA; SCLC; ncPRC1.6; tumor suppressor

DOI:  https://doi.org/10.1073/pnas.2024824118
Neuron. 2021 Sep 01. pii: S0896-6273(21)00608-5. [Epub ahead of print]

Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2.

Kelly A Chamberlain, Ning Huang, Yuxiang Xie, Francesca LiCausi, Sunan Li, Yan Li, Zu-Hang Sheng.

  Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Here, we elucidate a transcellular signaling mechanism by which oligodendrocytes support axonal energy metabolism via transcellular delivery of NAD-dependent deacetylase SIRT2. SIRT2 is undetectable in neurons but enriched in oligodendrocytes and released within exosomes. By deleting sirt2, knocking down SIRT2, or blocking exosome release, we demonstrate that transcellular delivery of SIRT2 is critical for axonal energy enhancement. Mass spectrometry and acetylation analyses indicate that neurons treated with oligodendrocyte-conditioned media from WT, but not sirt2-knockout, mice exhibit strong deacetylation of mitochondrial adenine nucleotide translocases 1 and 2 (ANT1/2). In vivo delivery of SIRT2-filled exosomes into myelinated axons rescues mitochondrial integrity in sirt2-knockout mouse spinal cords. Thus, our study reveals an oligodendrocyte-to-axon delivery of SIRT2, which enhances ATP production by deacetylating mitochondrial proteins, providing a target for boosting axonal bioenergetic metabolism in neurological disorders.

Keywords:  acetylation; adenine nucleotide translocases 1 and 2; axonal ATP; axonal energetics; axonal mitochondria; energy metabolism; exosome; myelin; oligodendrocyte; sirtuin 2

DOI:  https://doi.org/10.1016/j.neuron.2021.08.011
Epigenetics. 2021 Sep 08. 1-12

An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer.

Artem V Artemov, Svetlana Zhenilo, Daria Kaplun, Alexey Starshin, Alexey Sokolov, Alexander M Mazur, Justyna Szpotan, Maciej Gawronski, Martyna Modrzejewska, Daniel Gackowski, Egor B Prokhortchouk.

  Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene (VHL) by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We showed that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate - a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases.

Keywords:  DNA methylation; HIF1A; VHL; hypoxia; kidney cancer

DOI:  https://doi.org/10.1080/15592294.2021.1971372
Mitochondrion. 2021 Sep 06. pii: S1567-7249(21)00118-5. [Epub ahead of print]

Trapped topoisomerase-DNA covalent complexes in the mitochondria and their role in human diseases.

Benu Brata Das, Arijit Ghosh, Sangheeta Bhattacharjee, Arpan Bhattacharyya.

  Topoisomerases regulate DNA topology, organization of the intracellular DNA, the transmission of genetic materials, and gene expressions. Other than the nuclear genome, mitochondria also harbor the small, circular DNA (mtDNA) that encodes a critical subset of proteins for the production of cellular ATP; however, mitochondria are solely dependent on the nucleus for all the mitochondrial proteins necessary for mtDNA replication, repair, and maintenance. Mitochondrial genome compiles topological stress from bidirectional transcription and replication, therefore imports four nuclear encoded topoisomerases (Top1mt, Top2α, Top2β, and Top3α) in the mitochondria to relax mtDNA supercoiling generated during these processes. Trapping of topoisomerase on DNA results in the formation of protein-linked DNA adducts (PDAs), which are widely exploited by topoisomerase-targeting anticancer drugs. Intriguingly mtDNA is potentially exposed to DNA damage that has been attributed to a variety of human diseases, including neurodegeneration, cancer, and premature aging. In this review, we focus on the role of different topoisomerases in the mitochondria and our current understanding of the mitochondrial DNA damage through trapped protein-DNA complexes, and the progress in the molecular mechanisms of the repair for trapped topoisomerase covalent complexes (Topcc). Finally, we have discussed how the pathological DNA lesions that cause mtDNA damage,trigger mitochondrial fission and mitophagy, which serve as quality control events for clearing damaged mtDNA.

Keywords:  DNA repair; Mitochondria; TDP1; TDP2; TFAM; Topoisomerase 1; Topoisomerase II; mitochondrial DNA; neurological diseases

DOI:  https://doi.org/10.1016/j.mito.2021.08.017
Livers. 2021 ;1(3): 102-115

Mitochondrial Dynamics in Drug-Induced Liver Injury.

Anup Ramachandran, David S Umbaugh, Hartmut Jaeschke.

  Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

Keywords:  acetaminophen; drug-induced liver injury; fission; fusion; mitochondrial dynamics

DOI:  https://doi.org/10.3390/livers1030010
Aging (Albany NY). 2021 Sep 07. 13(undefined):

Glutathione is an aging-related metabolic signature in the mouse kidney.

Eunyong Ahn, Jueun Lee, Jisu Han, Seung-Min Lee, Ki-Sun Kwon, Geum-Sook Hwang.

  The ability to maintain systemic metabolic homeostasis through various mechanisms represents a crucial strength of kidneys in the study of metabolic syndrome or aging. Moreover, age-associated kidney failure has been widely accepted. However, efforts to demonstrate aging-dependent renal metabolic rewiring have been limited. In the present study, we investigated aging-related renal metabolic determinants by integrating metabolomic and transcriptomic data sets from kidneys of young (3 months, n = 7 and 3 for respectively) and old (24 months, n = 8 and 3 for respectively) naive C57BL/6 male mice. Metabolite profiling analysis was conducted, followed by data processing via network and pathway analyses, to identify differential metabolites. In the aged group, the levels of glutathione and oxidized glutathione were significantly increased, but the levels of gamma-glutamyl amino acids, amino acids combined with the gamma-glutamyl moiety from glutathione by membrane transpeptidases, and circulating glutathione levels were decreased. In transcriptomic analysis, differential expression of metabolic enzymes is consistent with the hypothesis of aging-dependent rewiring in renal glutathione metabolism; pathway and network analyses further revealed the increased expression of immune-related genes in the aged group. Collectively, our integrative analysis results revealed that defective renal glutathione metabolism is a signature of renal aging. Therefore, we hypothesize that restraining renal glutathione metabolism might alleviate or delay age-associated renal metabolic deterioration, and aberrant activation of the renal immune system.

Keywords:  glutathione metabolism; metabolomics; renal aging; transcriptomics

DOI:  https://doi.org/10.18632/aging.203509
Trends Cancer. 2021 Sep 01. pii: S2405-8033(21)00161-8. [Epub ahead of print]

Tilting MYC toward cancer cell death.

Colleen T Harrington, Elena Sotillo, Chi V Dang, Andrei Thomas-Tikhonenko.

  MYC oncoprotein promotes cell proliferation and serves as the key driver in many human cancers; therefore, considerable effort has been expended to develop reliable pharmacological methods to suppress its expression or function. Despite impressive progress, MYC-targeting drugs have not reached the clinic. Recent advances suggest that within a limited expression range unique to each tumor, MYC oncoprotein can have a paradoxical, proapoptotic function. Here we introduce a counterintuitive idea that modestly and transiently elevating MYC levels could aid chemotherapy-induced apoptosis and thus benefit the patients as much, if not more than MYC inhibition.

Keywords:  MYC; apoptosis, chemotherapy; oncogene addiction

DOI:  https://doi.org/10.1016/j.trecan.2021.08.002
FEBS J. 2021 Sep 08.

The nexus between redox state and intermediary metabolism.

Anna Zoccarato, Adam A Nabeebaccus, Rafael R Oexner, Celio Xc Santos, Ajay M Shah.

  Reactive oxygen species (ROS) are not just a by-product of cellular metabolic processes but act as signalling molecules that regulate both physiological and pathophysiological processes. A close connection exists in cells between redox homeostasis and cellular metabolism. In this review, we describe how intracellular redox state and glycolytic intermediary metabolism are closely coupled. On the one hand, ROS signalling can control glycolytic intermediary metabolism by direct regulation of the activity of key metabolic enzymes and indirect regulation via redox-sensitive transcription factors. On the other hand, metabolic adaptation and reprogramming in response to physiological or pathological stimuli regulate intracellular redox balance, through mechanisms such as the generation of reducing equivalents. We also discuss the impact of these intermediary metabolism-redox circuits in physiological and disease settings across different tissues. A better understanding of the mechanisms regulating these intermediary metabolism-redox circuits will be crucial to the development of novel therapeutic strategies.

Keywords:  Intermediary metabolism; Redox; Warburg effect; anabolism; reactive oxygen species

DOI:  https://doi.org/10.1111/febs.16191
Cancers (Basel). 2021 Sep 06. pii: 4484. [Epub ahead of print]13(17):

MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.

Vincent Tambay, Valérie-Ann Raymond, Marc Bilodeau.

  Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

Keywords:  MYC; glutamine metabolism; oncogene

DOI:  https://doi.org/10.3390/cancers13174484
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2011226118. [Epub ahead of print]118(37):

NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.

Yujun Hou, Yong Wei, Sofie Lautrup, Beimeng Yang, Yue Wang, Stephanie Cordonnier, Mark P Mattson, Deborah L Croteau, Vilhelm A Bohr.

  Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS-STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS-STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS-STING in neuroinflammation and cellular senescence in AD.

Keywords:  Alzheimer’s disease; DNA repair; NAD supplementation; inflammation; neurodegeneration

DOI:  https://doi.org/10.1073/pnas.2011226118
Cancer Cell. 2021 Sep 06. pii: S1535-6108(21)00446-3. [Epub ahead of print]

Microbiome and cancer.

Nyssa Cullin, Camila Azevedo Antunes, Ravid Straussman, Christoph K Stein-Thoeringer, Eran Elinav.

  The human microbiome constitutes a complex multikingdom community that symbiotically interacts with the host across multiple body sites. Host-microbiome interactions impact multiple physiological processes and a variety of multifactorial disease conditions. In the past decade, microbiome communities have been suggested to influence the development, progression, metastasis formation, and treatment response of multiple cancer types. While causal evidence of microbial impacts on cancer biology is only beginning to be unraveled, enhanced molecular understanding of such cancer-modulating interactions and impacts on cancer treatment are considered of major scientific importance and clinical relevance. In this review, we describe the molecular pathogenic mechanisms shared throughout microbial niches that contribute to the initiation and progression of cancer. We highlight advances, limitations, challenges, and prospects in understanding how the microbiome may causally impact cancer and its treatment responsiveness, and how microorganisms or their secreted bioactive metabolites may be potentially harnessed and targeted as precision cancer therapeutics.

Keywords:  cancer; microbiome; microbiome modifications; transkingdom crosstalk

DOI:  https://doi.org/10.1016/j.ccell.2021.08.006
Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00369-7. [Epub ahead of print]33(9): 1744-1762

Exosomes as mediators of intercellular crosstalk in metabolism.

Roi Isaac, Felipe Castellani Gomes Reis, Wei Ying, Jerrold M Olefsky.

Exosomes are nanoparticles secreted by all cell types and are a large component of the broader class of nanoparticles termed extracellular vesicles (EVs). Once secreted, exosomes gain access to the interstitial space and ultimately the circulation, where they exert local paracrine or distal systemic effects. Because of this, exosomes are important components of an intercellular and intraorgan communication system capable of carrying biologic signals from one cell type or tissue to another. The exosomal cargo consists of proteins, lipids, miRNAs, and other RNA species, and many of the biologic effects of exosomes have been attributed to miRNAs. Exosomal miRNAs have also been used as disease biomarkers. The field of exosome biology and metabolism is rapidly expanding, with new discoveries and reports appearing on a regular basis, and it is possible that potential therapeutic approaches for the use of exosomes or miRNAs in metabolic diseases will be initiated in the near future.

DOI: https://doi.org/10.1016/j.cmet.2021.08.006