bims-camemi 2020-12-06 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2020‒12‒06
48 papers selected by
Christian Frezza,

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.
The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer.
The Functional Impact of Mitochondrial Structure Across Subcellular Scales.
The molecular complexity of the Mitochondrial Calcium Uniporter.
Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells.
Mitochondria as a Platform for Dictating the Cell Fate of Cultured Human Corneal Endothelial Cells.
Circadian Rheb Oscillation Alters the Dynamics of Hepatic mTORC1 Activity and Mitochondrial Morphology.
Metabolomics revealed the influence of breast cancer on lymphatic endothelial cell metabolism, metabolic crosstalk, and lymphangiogenic signaling in co-culture.
Modulating NK cell metabolism for cancer immunotherapy.
Metabolic traits ruling the specificity of the immune response in different cancer types.
The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress.
Mitochondrial Damage and the Road to Exhaustion.
Mitochondrial oxidative function in NAFLD: friend or foe?
CDK1, the Other 'Master Regulator' of Autophagy.
Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity.
Low shear stress induced vascular endothelial cell pyroptosis by TET2/SDHB/ROS pathway.
SCENITH: A Flow Cytometry-Based Method to Functionally Profile Energy Metabolism with Single-Cell Resolution.
Adiponectin enhances the bioenergetics of cardiac myocytes via an AMPK and succinate dehydrogenase-dependnet mechanism.
Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.
Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer.
Location-specific inhibition of Akt reveals regulation of mTORC1 activity in the nucleus.
Dual function of GTPBP6 in biogenesis and recycling of human mitochondrial ribosomes.
IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis.
Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer.
Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression.
Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.
Ferrous Iron-Dependent Pharmacology.
Hierarchical routing in carbon metabolism favors iron-scavenging strategy in iron-deficient soil Pseudomonas species.
Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids.
Mutation-selection balance and compensatory mechanisms in tumour evolution.
Isocitrate Dehydrogenase 2 Inhibitors for the treatment of Hematologic Malignancies: Advances and Future Opportunities.
Mitochondria signaling to the epigenome: a novel role for an old organelle.
RIPK1 Promotes Energy Sensing by the mTORC1 Pathway.
Roadmap on multiscale coupling of biochemical and mechanical signals during development.
A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation.
Effect of Non-Enzymatic Glycosylation in the Epigenetics of Cancer.
Serine and Metabolism Regulation: A Novel Mechanism in Antitumor Immunity and Senescence.
The neuronal-metabolic interface.
Three-dimensional imaging of mitochondrial cristae complexity using cryo-soft X-ray tomography.
Supercomplex formation boosts respiration.
Mapping choline metabolites in normal and transformed cells.
Inhibiting enolase eradicates tumours.
Reversal of biological clock restores vision in old mice.
When a House Is Not a Home: A Survey of Antimetastatic Niches and Potential Mechanisms of Disseminated Tumor Cell Suppression.
Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy.
How to write a superb literature review.
DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity.
Reprogramming to recover youthful epigenetic information and restore vision.

Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30598-2. [Epub ahead of print]32(6): 981-995.e7

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.

Mauro Corrado, Joy Edwards-Hicks, Matteo Villa, Lea J Flachsmann, David E Sanin, Maaike Jacobs, Francesc Baixauli, Michal Stanczak, Eve Anderson, Mai Azuma, Andrea Quintana, Jonathan D Curtis, Thomas Clapes, Katarzyna M Grzes, Agnieszka M Kabat, Ryan Kyle, Annette E Patterson, Ramon Klein Geltink, Borko Amulic, Colin G Steward, Douglas Strathdee, Eirini Trompouki, David O'Sullivan, Edward J Pearce, Erika L Pearce.

  Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.

Keywords:  Barth Syndrome; CD8 T cells; PTPMT1; Tafazzin; cardiolipin; immune memory; immunometabolism; mitochodria

DOI:  https://doi.org/10.1016/j.cmet.2020.11.003
Nat Metab. 2020 Nov 30.

The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer.

Jiyeon Kim, Hyun Min Lee, Feng Cai, Bookyung Ko, Chendong Yang, Elizabeth L Lieu, Nefertiti Muhammad, Shawn Rhyne, Kailong Li, Mohamed Haloul, Wen Gu, Brandon Faubert, Akash K Kaushik, Ling Cai, Sahba Kasiri, Ummay Marriam, Kien Nham, Luc Girard, Hui Wang, Xiankai Sun, James Kim, John D Minna, Keziban Unsal-Kacmaz, Ralph J DeBerardinis.

In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumour suppressor STK11 (also known as LKB1) encoding the kinase LKB1 result in aggressive tumours prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analysed tumour metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KRAS/LKB1 co-mutant tumours. KRAS/LKB1 co-mutant cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme glutamine-fructose-6-phosphate transaminase [isomerizing] 2 (GFPT2). GFPT2 inhibition selectively reduced KRAS/LKB1 co-mutant tumour cell growth in culture, xenografts and genetically modified mice. Our results define a new metabolic vulnerability in KRAS/LKB1 co-mutant tumours and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.

DOI: https://doi.org/10.1038/s42255-020-00316-0
Front Physiol. 2020 ;11 541040

The Functional Impact of Mitochondrial Structure Across Subcellular Scales.

Brian Glancy, Yuho Kim, Prasanna Katti, T Bradley Willingham.

  Mitochondria are key determinants of cellular health. However, the functional role of mitochondria varies from cell to cell depending on the relative demands for energy distribution, metabolite biosynthesis, and/or signaling. In order to support the specific needs of different cell types, mitochondrial functional capacity can be optimized in part by modulating mitochondrial structure across several different spatial scales. Here we discuss the functional implications of altering mitochondrial structure with an emphasis on the physiological trade-offs associated with different mitochondrial configurations. Within a mitochondrion, increasing the amount of cristae in the inner membrane improves capacity for energy conversion and free radical-mediated signaling but may come at the expense of matrix space where enzymes critical for metabolite biosynthesis and signaling reside. Electrically isolating individual cristae could provide a protective mechanism to limit the spread of dysfunction within a mitochondrion but may also slow the response time to an increase in cellular energy demand. For individual mitochondria, those with relatively greater surface areas can facilitate interactions with the cytosol or other organelles but may be more costly to remove through mitophagy due to the need for larger phagophore membranes. At the network scale, a large, stable mitochondrial reticulum can provide a structural pathway for energy distribution and communication across long distances yet also enable rapid spreading of localized dysfunction. Highly dynamic mitochondrial networks allow for frequent content mixing and communication but require constant cellular remodeling to accommodate the movement of mitochondria. The formation of contact sites between mitochondria and several other organelles provides a mechanism for specialized communication and direct content transfer between organelles. However, increasing the number of contact sites between mitochondria and any given organelle reduces the mitochondrial surface area available for contact sites with other organelles as well as for metabolite exchange with cytosol. Though the precise mechanisms guiding the coordinated multi-scale mitochondrial configurations observed in different cell types have yet to be elucidated, it is clear that mitochondrial structure is tailored at every level to optimize mitochondrial function to meet specific cellular demands.

Keywords:  cristae; energetics; mitochondria; mitochondrial dynamics; mitochondrial networks; organelle interaction

DOI:  https://doi.org/10.3389/fphys.2020.541040
Cell Calcium. 2020 Nov 22. pii: S0143-4160(20)30164-0. [Epub ahead of print]93 102322

The molecular complexity of the Mitochondrial Calcium Uniporter.

Simona Feno, Rosario Rizzuto, Anna Raffaello, Denis Vecellio Reane.

  The role of mitochondria in regulating cellular Ca2+ homeostasis is crucial for the understanding of different cellular functions in physiological and pathological conditions. Nevertheless, the study of this aspect was severely limited by the lack of the molecular identity of the proteins responsible for mitochondrial Ca2+ uptake. In 2011, the discovery of the gene encoding for the Mitochondrial Calcium Uniporter (MCU), the selective channel responsible for mitochondrial Ca2+ uptake, gave rise to an explosion of studies aimed to characterize the composition, the regulation of the channel and its pathophysiological roles. Here, we summarize the recent discoveries on the molecular structure and composition of the MCU complex by providing new insights into the mechanisms that regulate MCU channel activity.

Keywords:  Calcium homeostasis; Mitochondria; Mitochondrial Calcium Uniporter

DOI:  https://doi.org/10.1016/j.ceca.2020.102322
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30594-5. [Epub ahead of print]32(6): 967-980.e5

Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells.

Bowen Wu, Jingtao Qiu, Tuantuan V Zhao, Yanan Wang, Toshihisa Maeda, Isabel N Goronzy, Mitsuhiro Akiyama, Shozo Ohtsuki, Ke Jin, Lu Tian, Jörg J Goronzy, Cornelia M Weyand.

  Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygen consumption and ATP production. Here, we identified suppression of the GDP-forming β subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficient T cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductive direction, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiated into pro-inflammatory effector cells. In AcCoAhi RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficient T cells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.

Keywords:  T cell; acetyl-CoA; acetylation; alph-ketoglutarate; autoimmunity; citrate; microtubule; mitochondria; tissue invasion; uropod

DOI:  https://doi.org/10.1016/j.cmet.2020.10.025
Invest Ophthalmol Vis Sci. 2020 Dec 01. 61(14): 10

Mitochondria as a Platform for Dictating the Cell Fate of Cultured Human Corneal Endothelial Cells.

Kohsaku Numa, Morio Ueno, Tomoko Fujita, Koji Ueda, Nao Hiramoto, Atushi Mukai, Yuichi Tokuda, Masakazu Nakano, Chie Sotozono, Shigeru Kinoshita, Junji Hamuro.

Purpose: Aiming to clarify the role of mitochondria in cell fate decision of cultured human corneal endothelial cell (cHCEC) subpopulations.Methods: The mitochondrial respiratory ability were examined with Mito stress and Mito fuel flex test assays using an extracellular flux analyzer (XFe24; Agilent Technologies; Santa Clara, CA) for human corneal endothelium tissues, mature cHCECs and a variety of cell state transitioned cHCECs. Tricarboxylic acid cycle and acetyl-coenzyme A-related enzymes was analyzed by proteomics for cell lysates using liquid chromatography-tandem mass spectrometry for cHCEC subpopulations.
Results: The maximum oxygen consumption rate was found to become stable depending on the maturation of cHCECs. In the Mito stress tests, culture supplements, epidermal growth factor, SB203580, and SB431543 significantly repressed oxygen consumption rate, whereas a Rho-associated protein kinase inhibitor Y-27632 increased. Tricarboxylic acid cycle and mitochondria acetyl-coenzyme A-related enzymes were selectively upregulated in mature cHCECs, but not in cell state transitioned cHCECs. The maximum oxygen consumption rate was found to be higher in healthy human corneal endothelium tissues than those with deeply reduced cell density. An upregulated tricarboxylic acid cycle was linked with metabolic rewiring converting cHCECs to acquire the mitochondria-dependent oxidative phenotype.
Conclusions: Mitochondrial metabolic intermediates and energy metabolism are tightly linked to the endothelial cell fate and function. These findings will help us to standardize a protocol for endothelial cell injection.

DOI: https://doi.org/10.1167/iovs.61.14.10
FEBS Lett. 2020 Nov 28.

Circadian Rheb Oscillation Alters the Dynamics of Hepatic mTORC1 Activity and Mitochondrial Morphology.

Qiuyun Yuan, Mina Chen, Wanchun Yang, Bo Xiao.

  The morphological structure and metabolic activity of mitochondria are coordinately regulated by circadian mechanisms. However, the mechanistic interplay between circadian mechanisms and mitochondrial architecture remains poorly understood. Here, we demonstrate circadian rhythmicity of Rheb protein in liver, in line with that of Per2. Using genetic mouse models, we show that Rheb, a small GTPase that binds mTOR, is critical for circadian oscillation of mTORC1 activity in liver. Disruption of Rheb oscillation in hepatocytes by persistent expression of Rheb transgene interrupted mTORC1 oscillation. We further show that Rheb-regulated mTORC1 altered mitochondrial fission factor DRP1 in liver, leading to altered mitochondrial dynamics. Our results suggest that Rheb/mTORC1 regulated DRP1 oscillation involves ubiquitin-mediated proteolysis. This study identifies Rheb as a nodal point that couples circadian clock and mitochondrial architecture for optimal mitochondrial metabolism.

Keywords:  Circadian clock; DRP1; Rheb/mTORC1; mitochondrial dynamics

DOI:  https://doi.org/10.1002/1873-3468.14009
Sci Rep. 2020 Dec 04. 10(1): 21244

Metabolomics revealed the influence of breast cancer on lymphatic endothelial cell metabolism, metabolic crosstalk, and lymphangiogenic signaling in co-culture.

Suehelay Acevedo-Acevedo, Douglas C Millar, Aaron D Simmons, Peter Favreau, Paulo F Cobra, Melissa Skala, Sean P Palecek.

Breast cancer metastasis occurs via blood and lymphatic vessels. Breast cancer cells 'educate' lymphatic endothelial cells (LECs) to support tumor vascularization and growth. However, despite known metabolic alterations in breast cancer, it remains unclear how lymphatic endothelial cell metabolism is altered in the tumor microenvironment and its effect in lymphangiogenic signaling in LECs. We analyzed metabolites inside LECs in co-culture with MCF-7, MDA-MB-231, and SK-BR-3 breast cancer cell lines using [Formula: see text] nuclear magnetic resonance (NMR) metabolomics, Seahorse, and the spatial distribution of metabolic co-enzymes using optical redox ratio imaging to describe breast cancer-LEC metabolic crosstalk. LECs co-cultured with breast cancer cells exhibited cell-line dependent altered metabolic profiles, including significant changes in lactate concentration in breast cancer co-culture. Cell metabolic phenotype analysis using Seahorse showed LECs in co-culture exhibited reduced mitochondrial respiration, increased reliance on glycolysis and reduced metabolic flexibility. Optical redox ratio measurements revealed reduced NAD(P)H levels in LECs potentially due to increased NAD(P)H utilization to maintain redox homeostasis. [Formula: see text]-labeled glucose experiments did not reveal lactate shuttling into LECs from breast cancer cells, yet showed other [Formula: see text] signals in LECs suggesting internalized metabolites and metabolic exchange between the two cell types. We also determined that breast cancer co-culture stimulated lymphangiogenic signaling in LECs, yet activation was not stimulated by lactate alone. Increased lymphangiogenic signaling suggests paracrine signaling between LECs and breast cancer cells which could have a pro-metastatic role.

DOI: https://doi.org/10.1038/s41598-020-76394-7
Semin Hematol. 2020 Oct;pii: S0037-1963(20)30041-X. [Epub ahead of print]57(4): 213-224

Modulating NK cell metabolism for cancer immunotherapy.

Iñigo Terrén, Ane Orrantia, Joana Vitallé, Gabirel Astarloa-Pando, Olatz Zenarruzabeitia, Francisco Borrego.

  Natural killer (NK) cells are lymphocytes with potent antitumor functions and, therefore, multiple NK cell-based cancer immunotherapies have been developed and are currently being tested. However, there is a necessity to find new means to improve these therapies, and immunometabolism represents an attractive target. NK cell effector functions are intricately linked to their metabolism, and modulating the latter could be the key to release their full potential. In this review, we have summarized how NK cell metabolism is regulated during some processes, such as maturation, viral infection, and cytokine stimulation. Additionally, we provide an overview of how NK cell metabolism is affected by current therapeutic approaches aimed to promote NK cell expansion and/or to increase their effector functions. We have also recapitulated several strategies that could help alleviating the metabolic impairment that characterizes tumor-infiltrating NK cells, and thus increase or restore their effector functions. Furthermore, we have reviewed several therapeutic approaches targeting cancer metabolism that could synergize with NK cell-based cancer immunotherapies, and thus enhance their efficacy.

Keywords:  CAR; NK cell-based cancer immunotherapy; NK cells; OXPHOS; glycolysis; lipid metabolism; metabolism

DOI:  https://doi.org/10.1053/j.seminhematol.2020.10.003
Curr Opin Biotechnol. 2020 Nov 25. pii: S0958-1669(20)30160-9. [Epub ahead of print]68 124-143

Metabolic traits ruling the specificity of the immune response in different cancer types.

Nina C Flerin, Federica Cappellesso, Samantha Pretto, Massimiliano Mazzone.

Cancer immunotherapy aims to augment the response of the patient's own immune system against cancer cells. Despite effective for some patients and some cancer types, the therapeutic efficacy of this treatment is limited by the composition of the tumor microenvironment (TME), which is not well-suited for the fitness of anti-tumoral immune cells. However, the TME differs between cancer types and tissues, thus complicating the possibility of the development of therapies that would be effective in a large range of patients. A possible scenario is that each type of cancer cell, granted by its own mutations and reminiscent of the functions of the tissue of origin, has a specific metabolism that will impinge on the metabolic composition of the TME, which in turn specifically affects T cell fitness. Therefore, targeting cancer or T cell metabolism could increase the efficacy and specificity of existing immunotherapies, improving disease outcome and minimizing adverse reactions.

DOI: https://doi.org/10.1016/j.copbio.2020.10.011
Cell Death Differ. 2020 Dec 02.

The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress.

Rita Moreno, Sourav Banerjee, Angus W Jackson, Jean Quinn, Gregg Baillie, Jack E Dixon, Albena T Dinkova-Kostova, Joanne Edwards, Laureano de la Vega.

To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target.

DOI: https://doi.org/10.1038/s41418-020-00686-8
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30599-4. [Epub ahead of print]32(6): 905-907

Mitochondrial Damage and the Road to Exhaustion.

Wenhui Li, Hongcheng Cheng, Guideng Li, Lianjun Zhang.

Two recent studies published in Nature Immunology map out the link between dysregulated mitochondrial metabolism and terminal exhaustion of tumor-infiltrating T lymphocytes. Yu et al. (2020) and Vardhana et al. (2020) show that defective mitophagy or impaired oxidative phosphorylation triggers mitochondrial reactive oxygen species production, which in turn promotes a T cell exhaustion program, limiting T cell proliferation and self-renewal.

DOI: https://doi.org/10.1016/j.cmet.2020.11.004
Mol Metab. 2020 Dec 01. pii: S2212-8778(20)30208-8. [Epub ahead of print] 101134

Mitochondrial oxidative function in NAFLD: friend or foe?

Michael Shum, Jennifer Ngo, Orian S Shirihai, Marc Liesa.

  BACKGROUND: Mitochondrial oxidative function plays a key role in the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance (IR). Recent studies support that fatty liver might not be a result of decreased mitochondrial fat oxidation caused by mitochondrial damage. Rather, NAFLD and IR cause an elevation in mitochondrial function, which covers the increased demand for carbon intermediates and ATP caused by elevated lipogenesis and gluconeogenesis. Furthermore, mitochondria play a role regulating hepatic insulin sensitivity and lipogenesis by modulating redox-sensitive signaling pathways.SCOPE OF REVIEW: We review the contradictory studies indicating that NAFLD and hyperglycemia can either increase or decrease mitochondrial oxidative capacity in liver. We summarize mechanisms regulating mitochondrial heterogeneity inside the same cell and discuss how these mechanisms may determine the role of mitochondria in NAFLD. We further discuss the role of endogenous antioxidants in the control of mitochondrial H2O2 release and redox-mediated signaling. Finally, we describe the emerging concept that the subcellular location of cellular antioxidants is a key determinant of their effects on NAFLD.
MAJOR CONCLUSIONS: The balance of fat oxidation versus accumulation is dependent on mitochondrial fuel preference, rather than ATP-synthesizing respiration. As such, therapies targeting fuel preference might be more suitable to treat NAFLD. Similarly, suppressing maladaptive antioxidants, rather than interfering with physiological mitochondrial H2O2-mediated signaling, may allow for the maintenance of intact hepatic insulin signaling in NAFLD. Exploration of sub-cellular compartmentalization of different antioxidant systems and the unique functions of specific mitochondrial sub-populations may offer new points of intervention to treat NAFLD.

Keywords:  H(2)O(2); NAFLD; NASH; lipid metabolism; mitochondria; mitochondrial heterogeneity; mitophagy

DOI:  https://doi.org/10.1016/j.molmet.2020.101134
Trends Cell Biol. 2020 Nov 30. pii: S0962-8924(20)30226-9. [Epub ahead of print]

CDK1, the Other 'Master Regulator' of Autophagy.

Richard I Odle, Oliver Florey, Nicholas T Ktistakis, Simon J Cook.

  Autophagy and cap-dependent mRNA translation are tightly regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signalling complex in response to nutrient availability. However, the regulation of these processes, and mTORC1 itself, is different during mitosis, and this has remained an area of significant controversy; for example, studies have argued that autophagy is either repressed or highly active during mitosis. Recent studies have shown that autophagy initiation is repressed, and cap-dependent mRNA translation is maintained during mitosis despite mTORC1 activity being repressed. This is achieved in large part by a switch from mTORC1- to cyclin-dependent kinase 1 (CDK1)-mediated regulation. Here, we review the history and recent advances and seek to present a unifying model to inform the future study of autophagy and mTORC1 during mitosis.

Keywords:  CDK1; autophagy; mTORC1; mitosis; translation

DOI:  https://doi.org/10.1016/j.tcb.2020.11.001
Sci Signal. 2020 Dec 01. pii: eaaz1236. [Epub ahead of print]13(660):

Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity.

Toshiya Kokaji, Atsushi Hatano, Yuki Ito, Katsuyuki Yugi, Miki Eto, Keigo Morita, Satoshi Ohno, Masashi Fujii, Ken-Ichi Hironaka, Riku Egami, Akira Terakawa, Takaho Tsuchiya, Haruka Ozaki, Hiroshi Inoue, Shinsuke Uda, Hiroyuki Kubota, Yutaka Suzuki, Kazutaka Ikeda, Makoto Arita, Masaki Matsumoto, Keiichi I Nakayama, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda.

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme-encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.

DOI: https://doi.org/10.1126/scisignal.aaz1236
Free Radic Biol Med. 2020 Nov 25. pii: S0891-5849(20)31629-4. [Epub ahead of print]

Low shear stress induced vascular endothelial cell pyroptosis by TET2/SDHB/ROS pathway.

Jinna Chen, Jianwu Zhang, Jiaxiong Wu, Shulei Zhang, Yamin Liang, Bin Zhou, Peng Wu, Dangheng Wei.

  Vascular endothelial cell (VEC) inflammation induced by low shear stress plays key roles in the initiation and progression of atherosclerosis (As). Pyroptosis is a form of inflammatory programmed cell death that is critical for As. However, the effect of low shear stress on VEC pyroptosis and the underlying mechanisms were not clear. Here we show that low shear stress promoted VEC pyroptosis and reduced the expression of Ten-Eleven Translocation 2 (TET2) methylcytosine dioxygenase. Loss of TET2 resulted in the upregulation of the expression and activity of mitochondrial respiratory complex II subunit succinate dehydrogenase B (SDHB) by decreasing the recruitment of histone deacetylase 2, independent of DNA demethylation modification. The overexpression of SDHB mediated mitochondrial injury and increased the production of reactive oxygen species (ROS). The administration of ROS scavenger NAC alleviated VEC pyroptosis induced by SDHB overexpression and TET2 shRNA. These findings show that low shear stress induced endothelial cell pyroptosis through the TET2/SDHB/ROS pathway and offer new insights into As.

Keywords:  Low shear stress; Mitochondrial injury; Pyroptosis; Reactive oxygen species; Succinate dehydrogenase B; Ten-Eleven Translocation 2; Vascular endothelial cell

DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.11.017
Cell Metab. 2020 Dec 01. pii: S1550-4131(20)30602-1. [Epub ahead of print]32(6): 1063-1075.e7

SCENITH: A Flow Cytometry-Based Method to Functionally Profile Energy Metabolism with Single-Cell Resolution.

Rafael J Argüello, Alexis J Combes, Remy Char, Julien-Paul Gigan, Ania I Baaziz, Evens Bousiquot, Voahirana Camosseto, Bushra Samad, Jessica Tsui, Peter Yan, Sebastien Boissonneau, Dominique Figarella-Branger, Evelina Gatti, Emeline Tabouret, Matthew F Krummel, Philippe Pierre.

  Energetic metabolism reprogramming is critical for cancer and immune responses. Current methods to functionally profile the global metabolic capacities and dependencies of cells are performed in bulk. We designed a simple method for complex metabolic profiling called SCENITH, for single-cell energetic metabolism by profiling translation inhibition. SCENITH allows for the study of metabolic responses in multiple cell types in parallel by flow cytometry. SCENITH is designed to perform metabolic studies ex vivo, particularly for rare cells in whole blood samples, avoiding metabolic biases introduced by culture media. We analyzed myeloid cells in solid tumors from patients and identified variable metabolic profiles, in ways that are not linked to their lineage or their activation phenotype. SCENITH's ability to reveal global metabolic functions and determine complex and linked immune-phenotypes in rare cell subpopulations will contribute to the information needed for evaluating therapeutic responses or patient stratification.

Keywords:  cell culture media and metabolism; functional assay metabolism single cells; metabolic function by flow cytometry; metabolic gene signatures; metabolic profiling of blood samples; metabolism analysis in samples from patients; protein synthesis and metabolism; translation and metabolism; tumor immunometabolism

DOI:  https://doi.org/10.1016/j.cmet.2020.11.007
Cell Signal. 2020 Nov 30. pii: S0898-6568(20)30343-0. [Epub ahead of print] 109866

Adiponectin enhances the bioenergetics of cardiac myocytes via an AMPK and succinate dehydrogenase-dependnet mechanism.

Yong Heui Jeon, Minzhen He, Julianne Austin, Hyewon Shin, Jessica Pfleger, Maha Abdellatif.

  Adiponectin is one of the most abundant circulating hormones, which through adenosine monophosphate-activated protein kinase (AMPK), enhances fatty acid and glucose oxidation, and exerts a cardioprotective effect. However, its effects on cellular bioenergetics have not been explored. We have previously reported that AMPK enhances mitochondrial respiration through a succinate dehydrogenase (SDH or complex II)-dependent mechanism in cardiac myocytes, leading us to predict that Adiponectin would exert a similar effect via activating AMPK. Our results show that Adiponectin enhances basal mitochondrial oxygen consumption rate (OCR), ATP production, and spare respiratory capacity (SRC), which were all abolished by the knockdown of AMPKγ1, inhibition of SDH complex assembly, via the knockdown of the SDH assembly factor 1 (Sdhaf1), or inhibition of SDH activity. Additionally, Adiponectin alleviated hypoxia-induced reductions in OCR and ATP production, in a Sdhaf1-dependent manner, whereas overexpression of Sdhaf1 confirmed its sufficiency for mediating these effects. Importantly, the levels of holoenzyme SDH under the various conditions correlated with OCR. We also show that the effects of Adiponectin, AMPK, Sdhaf1, as well as, SDH complex assembly all required sirtuin 3 (Sirt3). In conclusion, Adiponectin potentiates mitochondrial bioenergetics via promoting SDH complex assembly in an AMPK-, Sdhaf1-, and Sirt3-dependent fashion in cardiac myocytes.

Keywords:  AMPK; Adiponectin; Bioenergetics; Complex II; Oxygen consumption rate; Prkag1; Sdhaf1; Sirt3; Succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.cellsig.2020.109866
Nat Commun. 2020 11 30. 11(1): 6092

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.

Jared S Mackenzie, Dirk A Lamprecht, Rukaya Asmal, John H Adamson, Khushboo Borah, Dany J V Beste, Bei Shi Lee, Kevin Pethe, Simon Rousseau, Inna Krieger, James C Sacchettini, Joel N Glasgow, Adrie J C Steyn.

The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using 13C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically vulnerable state susceptible to genetic disruption of glycolysis and gluconeogenesis. Metabolic flux profiles indicate that BDQ-treated Mtb is dependent on glycolysis for ATP production, operates a bifurcated TCA cycle by increasing flux through the glyoxylate shunt, and requires enzymes of the anaplerotic node and methylcitrate cycle. Targeting oxidative phosphorylation (OXPHOS) with BDQ and simultaneously inhibiting substrate level phosphorylation via genetic disruption of glycolysis leads to rapid sterilization. Our findings provide insight into the metabolic mechanism of BDQ-induced cell death and establish a paradigm for the development of combination therapies that target OXPHOS and glycolysis.

DOI: https://doi.org/10.1038/s41467-020-19959-4
Nat Commun. 2020 Dec 04. 11(1): 6216

Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer.

Sanja Pajovic, Robert Siddaway, Taylor Bridge, Javal Sheth, Patricia Rakopoulos, Byungjin Kim, Scott Ryall, Sameer Agnihotri, Lauren Phillips, Man Yu, Christopher Li, Scott Milos, Palak Patel, Dilakshan Srikanthan, Annie Huang, Cynthia Hawkins.

Histone H3 lysine 27 (H3K27M) mutations represent the canonical oncohistone, occurring frequently in midline gliomas but also identified in haematopoietic malignancies and carcinomas. H3K27M functions, at least in part, through widespread changes in H3K27 trimethylation but its role in tumour initiation remains obscure. To address this, we created a transgenic mouse expressing H3.3K27M in diverse progenitor cell populations. H3.3K27M expression drives tumorigenesis in multiple tissues, which is further enhanced by Trp53 deletion. We find that H3.3K27M epigenetically activates a transcriptome, enriched for PRC2 and SOX10 targets, that overrides developmental and tissue specificity and is conserved between H3.3K27M-mutant mouse and human tumours. A key feature of the H3K27M transcriptome is activation of a RAS/MYC axis, which we find can be targeted therapeutically in isogenic and primary DIPG cell lines with H3.3K27M mutations, providing an explanation for the common co-occurrence of alterations in these pathways in human H3.3K27M-driven cancer. Taken together, these results show how H3.3K27M-driven transcriptome remodelling promotes tumorigenesis and will be critical for targeting cancers with these mutations.

DOI: https://doi.org/10.1038/s41467-020-19972-7
Nat Commun. 2020 11 30. 11(1): 6088

Location-specific inhibition of Akt reveals regulation of mTORC1 activity in the nucleus.

Xin Zhou, Yanghao Zhong, Olivia Molinar-Inglis, Maya T Kunkel, Mingyuan Chen, Tengqian Sun, Jiao Zhang, John Y-J Shyy, JoAnn Trejo, Alexandra C Newton, Jin Zhang.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth, nutrient and energy status cues to control cell growth and metabolism. While mTORC1 activation at the lysosome is well characterized, it is not clear how this complex is regulated at other subcellular locations. Here, we combine location-selective kinase inhibition, live-cell imaging and biochemical assays to probe the regulation of growth factor-induced mTORC1 activity in the nucleus. Using a nuclear targeted Akt Substrate-based Tandem Occupancy Peptide Sponge (Akt-STOPS) that we developed for specific inhibition of Akt, a critical upstream kinase, we show that growth factor-stimulated nuclear mTORC1 activity requires nuclear Akt activity. Further mechanistic dissection suggests that nuclear Akt activity mediates growth factor-induced nuclear translocation of Raptor, a regulatory scaffolding component in mTORC1, and localization of Raptor to the nucleus results in nuclear mTORC1 activity in the absence of growth factor stimulation. Taken together, these results reveal a mode of regulation of mTORC1 that is distinct from its lysosomal activation, which controls mTORC1 activity in the nuclear compartment.

DOI: https://doi.org/10.1038/s41467-020-19937-w
Nucleic Acids Res. 2020 Dec 02. pii: gkaa1132. [Epub ahead of print]

Dual function of GTPBP6 in biogenesis and recycling of human mitochondrial ribosomes.

Elena Lavdovskaia, Kärt Denks, Franziska Nadler, Emely Steube, Andreas Linden, Henning Urlaub, Marina V Rodnina, Ricarda Richter-Dennerlein.

Translation and ribosome biogenesis in mitochondria require auxiliary factors that ensure rapid and accurate synthesis of mitochondrial proteins. Defects in translation are associated with oxidative phosphorylation deficiency and cause severe human diseases, but the exact roles of mitochondrial translation-associated factors are not known. Here we identify the functions of GTPBP6, a homolog of the bacterial ribosome-recycling factor HflX, in human mitochondria. Similarly to HflX, GTPBP6 facilitates the dissociation of ribosomes in vitro and in vivo. In contrast to HflX, GTPBP6 is also required for the assembly of mitochondrial ribosomes. GTPBP6 ablation leads to accumulation of late assembly intermediate(s) of the large ribosomal subunit containing ribosome biogenesis factors MTERF4, NSUN4, MALSU1 and the GTPases GTPBP5, GTPBP7 and GTPBP10. Our data show that GTPBP6 has a dual function acting in ribosome recycling and biogenesis. These findings contribute to our understanding of large ribosomal subunit assembly as well as ribosome recycling pathway in mitochondria.

DOI: https://doi.org/10.1093/nar/gkaa1132
Blood. 2020 Nov 30. pii: blood.2020007075. [Epub ahead of print]

IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis.

Yu Gu, Risheng Yang, Ying Yang, Yuanlin Zhao, Andrew Wakeham, Wanda Y Li, Alan Tseng, Julie Leca, Thorsten Berger, Mary Saunders, Jerome Fortin, Xing Gao, Yuan Yuan, Liming Xiao, Feng Zhang, Lijun Zhang, Guangxun Gao, Wenjing Zhou, Zhe Wang, Tak W Mak, Jing Ye.

Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, increased immature progenitor and erythroblast. In erythroid cells of these mice, D-2-hydroxyglutarate (D-2HG), an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase (OGDH) activity and diminishes succinyl-CoA production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells (HSC), while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 (HO-1) expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species (ROS) that induce the cell death of IDH1-mutant erythroid cells. Our results clearly demonstrate the essential role of IDH1 in normal erythropoiesis and show how its mutation leads to myeloid disorders. Our data thus have important implications for the devising of new treatments for IDH-mutant tumors.

DOI: https://doi.org/10.1182/blood.2020007075
Cell Rep. 2020 Dec 01. pii: S2211-1247(20)31433-9. [Epub ahead of print]33(9): 108444

Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer.

Corrin A Wohlhieter, Allison L Richards, Fathema Uddin, Christopher H Hulton, Àlvaro Quintanal-Villalonga, Axel Martin, Elisa de Stanchina, Umeshkumar Bhanot, Marina Asher, Nisargbhai S Shah, Omar Hayatt, Darren J Buonocore, Natasha Rekhtman, Ronglai Shen, Kathryn C Arbour, Mark Donoghue, John T Poirier, Triparna Sen, Charles M Rudin.

  Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. We investigated the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3. Together these data identify SCD1 as a selective vulnerability and a promising candidate for targeted drug development in STK11/KEAP1 co-mutant LUAD.

Keywords:  AKR1C1; CRISPR; KEAP1; LKB1; NSCLC; SCD1; STK11; ferroptosis

DOI:  https://doi.org/10.1016/j.celrep.2020.108444
Nat Mater. 2020 Nov 30.

Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression.

Ori Maller, Allison P Drain, Alexander S Barrett, Signe Borgquist, Brian Ruffell, Igor Zakharevich, Thanh T Pham, Tina Gruosso, Hellen Kuasne, Johnathon N Lakins, Irene Acerbi, J Matthew Barnes, Travis Nemkov, Aastha Chauhan, Jessica Gruenberg, Aqsa Nasir, Olof Bjarnadottir, Zena Werb, Peter Kabos, Yunn-Yi Chen, E Shelley Hwang, Morag Park, Lisa M Coussens, Andrew C Nelson, Kirk C Hansen, Valerie M Weaver.

Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.

DOI: https://doi.org/10.1038/s41563-020-00849-5
Sci Adv. 2020 Dec;pii: eabc9207. [Epub ahead of print]6(49):

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

DDD Study

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

DOI: https://doi.org/10.1126/sciadv.abc9207
Trends Pharmacol Sci. 2020 Nov 28. pii: S0165-6147(20)30253-4. [Epub ahead of print]

Ferrous Iron-Dependent Pharmacology.

Ryan L Gonciarz, Eric A Collisson, Adam R Renslo.

  The recent emergence of oxidation state selective probes of cellular iron has produced a more nuanced understanding of how cells utilize this crucial nutrient to empower enzyme function, and also how labile ferrous iron contributes to iron-dependent cell death (ferroptosis) and other disease pathologies including cancer, bacterial infections, and neurodegeneration. These findings, viewed in light of the Fenton chemistry promoted by ferrous iron, suggest a new category of therapeutics exhibiting ferrous iron-dependent pharmacology. While still in its infancy, this nascent field draws inspiration from the remarkable activity and tremendous clinical impact of the antimalarial artemisinin. Here, we review recent insights into the role of labile ferrous iron in biology and disease, and describe new therapeutic approaches designed to exploit this divalent transition metal.

Keywords:  activity-based probes; ferritinophagy; ferroptosis; iron homeostasis; reactivity-based probes; targeted prodrugs

DOI:  https://doi.org/10.1016/j.tips.2020.11.003
Proc Natl Acad Sci U S A. 2020 Dec 03. pii: 202016380. [Epub ahead of print]

Hierarchical routing in carbon metabolism favors iron-scavenging strategy in iron-deficient soil Pseudomonas species.

Caroll M Mendonca, Sho Yoshitake, Hua Wei, Anne Werner, Samantha S Sasnow, Theodore W Thannhauser, Ludmilla Aristilde.

  High-affinity iron (Fe) scavenging compounds, or siderophores, are widely employed by soil bacteria to survive scarcity in bioavailable Fe. Siderophore biosynthesis relies on cellular carbon metabolism, despite reported decrease in both carbon uptake and Fe-containing metabolic proteins in Fe-deficient cells. Given this paradox, the metabolic network required to sustain the Fe-scavenging strategy is poorly understood. Here, through multiple 13C-metabolomics experiments with Fe-replete and Fe-limited cells, we uncover how soil Pseudomonas species reprogram their metabolic pathways to prioritize siderophore biosynthesis. Across the three species investigated (Pseudomonas putida KT2440, Pseudomonas protegens Pf-5, and Pseudomonas putida S12), siderophore secretion is higher during growth on gluconeogenic substrates than during growth on glycolytic substrates. In response to Fe limitation, we capture decreased flux toward the tricarboxylic acid (TCA) cycle during the metabolism of glycolytic substrates but, due to carbon recycling to the TCA cycle via enhanced anaplerosis, the metabolism of gluconeogenic substrates results in an increase in both siderophore secretion (up to threefold) and Fe extraction (up to sixfold) from soil minerals. During simultaneous feeding on the different substrate types, Fe deficiency triggers a hierarchy in substrate utilization, which is facilitated by changes in protein abundances for substrate uptake and initial catabolism. Rerouted metabolism further promotes favorable fluxes in the TCA cycle and the gluconeogenesis-anaplerosis nodes, despite decrease in several proteins in these pathways, to meet carbon and energy demands for siderophore precursors in accordance with increased proteins for siderophore biosynthesis. Hierarchical carbon metabolism thus serves as a critical survival strategy during the metal nutrient deficiency.

Keywords:  Pseudomonas putida; bacteria; iron limitation; metabolomics; siderophore

DOI:  https://doi.org/10.1073/pnas.2016380117
Proc Natl Acad Sci U S A. 2020 Dec 02. pii: 202013968. [Epub ahead of print]

Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids.

Simon Dusséaux, William Thomas Wajn, Yixuan Liu, Codruta Ignea, Sotirios C Kampranis.

  Current approaches for the production of high-value compounds in microorganisms mostly use the cytosol as a general reaction vessel. However, competing pathways and metabolic cross-talk frequently prevent efficient synthesis of target compounds in the cytosol. Eukaryotic cells control the complexity of their metabolism by harnessing organelles to insulate biochemical pathways. Inspired by this concept, herein we transform yeast peroxisomes into microfactories for geranyl diphosphate-derived compounds, focusing on monoterpenoids, monoterpene indole alkaloids, and cannabinoids. We introduce a complete mevalonate pathway in the peroxisome to convert acetyl-CoA to several commercially important monoterpenes and achieve up to 125-fold increase over cytosolic production. Furthermore, peroxisomal production improves subsequent decoration by cytochrome P450s, supporting efficient conversion of (S)-(-)-limonene to the menthol precursor trans-isopiperitenol. We also establish synthesis of 8-hydroxygeraniol, the precursor of monoterpene indole alkaloids, and cannabigerolic acid, the cannabinoid precursor. Our findings establish peroxisomal engineering as an efficient strategy for the production of isoprenoids.

Keywords:  compartmentalization; metabolic engineering; mevalonate pathway; synthetic biology; terpenoid

DOI:  https://doi.org/10.1073/pnas.2013968117
Nat Rev Genet. 2020 Nov 30.

Mutation-selection balance and compensatory mechanisms in tumour evolution.

Erez Persi, Yuri I Wolf, David Horn, Eytan Ruppin, Francesca Demichelis, Robert A Gatenby, Robert J Gillies, Eugene V Koonin.

Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mutations to whole-genome duplications, in tumour initiation and progression is lacking. We posit that different genomic aberrations generally exhibit a temporal order, shaped by a balance between the levels of mutations and selective pressures. Repeat instability emerges first, followed by larger aberrations, with compensatory effects leading to robust tumour fitness maintained throughout the tumour progression. A better understanding of the interplay between genetic aberrations, the microenvironment, and epigenetic and metabolic cellular states is essential for early detection and prevention of cancer as well as development of efficient therapeutic strategies.

DOI: https://doi.org/10.1038/s41576-020-00299-4
Mini Rev Med Chem. 2020 Nov 29.

Isocitrate Dehydrogenase 2 Inhibitors for the treatment of Hematologic Malignancies: Advances and Future Opportunities.

Feng Huang, Tian Tian, Yizhe Wu, Jinxin Che, Haiyan Yang, Xiaowu Dong.

  Tumor cells frequently reprogram cellular metabolism from oxidative phosphorylation to glycolysis. Isocitrate dehydrogenase 2 (IDH2) has been intensely studied due to its involvement in the metabolic activity of cancer cells. Mutations in IDH2 promote neomorphic activity through the generation of oncometabolite 2-hydroxyglutarate (2-HG). The overproduced 2-HG can competitively inhibit α-KG-dependent dioxygenases to trigger cell differentiation disorders, a major cause of blood tumors. This review outlines recent progress in the identification of IDH2 inhibitors in blood cancer to provide reference for ongoing and future clinical studies.

Keywords:  Blood Cancer. ; IDH2; Mutant; Inhibitors; Isocitrate Dehydrogenase 2; Structure-activity relationship

DOI:  https://doi.org/10.2174/1389557520666201130102724
Free Radic Biol Med. 2020 Nov 30. pii: S0891-5849(20)31628-2. [Epub ahead of print]

Mitochondria signaling to the epigenome: a novel role for an old organelle.

Janine Hertzog Santos.

Epigenetic modifications influence gene expression programs ultimately dictating physiological outcomes. In the past decades, an increasing body of work has demonstrated that the enzymes that deposit and/or remove epigenetic marks on DNA or histones use metabolites as substrates or co-factors, rendering the epigenome sensitive to metabolic changes. In this context, acetyl-CoA and α-ketoglutarate have been recognized as critical for epigenetics, impinging on histone marks and nuclear DNA methylation patterns. Given that these metabolites are primarily generated in the mitochondria through the tricarboxylic acid cycle (TCA), the requirement of proper mitochondrial function for maintenance of the epigenetic landscape seems obvious. Nevertheless, it was not until recently when the epigenomic outcomes of mitochondrial dysfunction were tested, revealing mitochondria's far-reaching impact on epigenetics. This review will focus on data that directly tested the role of mitochondria on the epigenetic landscape, the mechanisms by which mitochondrial dysfunction may dysregulate the epigenome and gene expression, and their potential implications to health and disease.

DOI: https://doi.org/10.1016/j.freeradbiomed.2020.11.016
Mol Cell. 2020 Nov 23. pii: S1097-2765(20)30786-3. [Epub ahead of print]

RIPK1 Promotes Energy Sensing by the mTORC1 Pathway.

Ayaz Najafov, Hoang Son Luu, Adnan K Mookhtiar, Lauren Mifflin, Hong-Guang Xia, Palak P Amin, Alban Ordureau, Huibing Wang, Junying Yuan.

  The mechanisms of cellular energy sensing and AMPK-mediated mTORC1 inhibition are not fully delineated. Here, we discover that RIPK1 promotes mTORC1 inhibition during energetic stress. RIPK1 is involved in mediating the interaction between AMPK and TSC2 and facilitate TSC2 phosphorylation at Ser1387. RIPK1 loss results in a high basal mTORC1 activity that drives defective lysosomes in cells and mice, leading to accumulation of RIPK3 and CASP8 and sensitization to cell death. RIPK1-deficient cells are unable to cope with energetic stress and are vulnerable to low glucose levels and metformin. Inhibition of mTORC1 rescues the lysosomal defects and vulnerability to energetic stress and prolongs the survival of RIPK1-deficient neonatal mice. Thus, RIPK1 plays an important role in the cellular response to low energy levels and mediates AMPK-mTORC1 signaling. These findings shed light on the regulation of mTORC1 during energetic stress and unveil a point of crosstalk between pro-survival and pro-death pathways.

Keywords:  AMPK; CASP8; MLKL; RIPK1; RIPK3; TSC2; lysosome; mTORC1; neonatal lethality

DOI:  https://doi.org/10.1016/j.molcel.2020.11.008
Phys Biol. 2020 Dec 04.

Roadmap on multiscale coupling of biochemical and mechanical signals during development.

Pierre François Lenne, Ed Munro, Idse Heemskerk, Aryeh Warmflash, Laura Bocanegra-Moreno, Kasumi Kishi, Anna Kicheva, Yuchen Long, Antoine Fruleux, Arezki Boudaoud, Timothy E Saunders, Paolo Caldarelli, Arthur Michaut, Jerome Gros, Yonit Maroudas-Sacks, Kinneret Keren, Edouard Hannezo, Zev J Gartner, Benjamin Stormo Stormo, Amy Gladfelter Gladfelter, Alan Rodrigues, Amy Shyer, Nicolas Minc, Jean-Léon Maître, Stefano Di Talia, Bassma Khamaisi, David Sprinzak, Sham Tlili.

  How interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models for how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this Roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface of the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms and modes of development. Together, these contributions highlight the many ways in which dynamic coupling of mechanics and biochemistry shape biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development.

Keywords:  Embryogenesis; Morphogenesis; Signalling

DOI:  https://doi.org/10.1088/1478-3975/abd0db
Nat Commun. 2020 12 02. 11(1): 6161

A human tissue map of 5-hydroxymethylcytosines exhibits tissue specificity through gene and enhancer modulation.

Xiao-Long Cui, Ji Nie, Jeremy Ku, Urszula Dougherty, Diana C West-Szymanski, Francois Collin, Christopher K Ellison, Laura Sieh, Yuhong Ning, Zifeng Deng, Carolyn W T Zhao, Anna Bergamaschi, Joel Pekow, Jiangbo Wei, Alana V Beadell, Zhou Zhang, Geeta Sharma, Raman Talwar, Patrick Arensdorf, Jason Karpus, Ajay Goel, Marc Bissonnette, Wei Zhang, Samuel Levy, Chuan He.

DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers.

DOI: https://doi.org/10.1038/s41467-020-20001-w
Semin Cancer Biol. 2020 Dec 01. pii: S1044-579X(20)30257-1. [Epub ahead of print]

Effect of Non-Enzymatic Glycosylation in the Epigenetics of Cancer.

Shahnawaz Rehman, Mohammad Aatif, Zeeshan Rafi, Mohd Yasir Khan, Uzma Shahab, Saheem Ahmad, Mohd Farhan.

  The non-enzymatic glycosylation or non-enzymatic covalent modifications (NECMs) or glycation of cellular proteins result in the generation and accumulation of advanced glycation end products (AGEs) that are associated with the epigenetics of cancer. Epigenetic modifications are inheritable changes without alterations in the sequences of DNA. Glycation-mediated epigenetic mechanisms change the accessibility of transcriptional factors to DNA via rearrangement or modification in the chromatin structure and collaborate with gene regulation in the pathogenesis of cancer. Epigenetic mechanisms play a critical role in sustaining the tissue-specific gene expression. Distraction from normal epigenetic mechanism results in alteration of gene function, initiation and progression of cancer, and cellular malignant transformation. Epigenetic modifications on DNA and histones control enzymatic expressions of corresponding metabolic pathways, which in turn influence epigenetic regulation. Glycation of histones due to persistent hyperglycemia results in histone-histone and histone-DNA cross-linking in chromatin by compromising the electrostatic interactions, that affect the dynamic architecture of chromatin. Histone proteins are highly prone to glycation due to their basic nature and long half-lives, but the exact role of histone glycation in the epigenetics of cancer is still in the veil. However, recent studies have suggested the role of histone glycation mediated epigenetic modifications that affect cellular functioning by altering the gene expressions of related metabolic pathways. Moreover, dicarbonyls-induced NECMs of histones perturb the architecture of chromatin and transcription of genes via multiple mechanisms. Contrary to the genetic causes of cancer, a possible reversal of glycation-mediated epigenetic modifications might open a new realm for therapeutic interventions. In this review, we have portrayed a mechanistic link between histone glycation and cancer epigenetics.

Keywords:  AGEs; Cancer; Epigenetics; Glycosylation; Histone

DOI:  https://doi.org/10.1016/j.semcancer.2020.11.019
Aging Dis. 2020 Dec;11(6): 1640-1653

Serine and Metabolism Regulation: A Novel Mechanism in Antitumor Immunity and Senescence.

Qi Wu, Xinyue Chen, Juanjuan Li, Shengrong Sun.

  As one of the nonessential amino acids (NEAAs), serine is involved in the anabolism of multiple macromolecular substances by participating in one-carbon unit metabolism. Thus, rapidly proliferating cells such as tumor cells and activated immune cells are highly dependent on serine. Serine supports the proliferation of various immune cells through multiple pathways to enhance the antitumor immune response. Moreover, serine influences aging specificity in an epigenetic and metabolic manner. In this review, we focus on recent advances in the relationship between serine metabolism, antitumor immunity, and senescence. The metabolic regulation of serine seems to be a key point of intervention in antitumor immunity and aging-related disease, providing an opportunity for several novel therapeutics.

Keywords:  Serine; antitumor immunity and senescence; metabolism

DOI:  https://doi.org/10.14336/AD.2020.0314
Nat Rev Cancer. 2020 Dec 01.

The neuronal-metabolic interface.

Ulrike Harjes.

DOI: https://doi.org/10.1038/s41568-020-00324-y
Sci Rep. 2020 Dec 03. 10(1): 21045

Three-dimensional imaging of mitochondrial cristae complexity using cryo-soft X-ray tomography.

Carla C Polo, Miriam H Fonseca-Alaniz, Jian-Hua Chen, Axel Ekman, Gerry McDermott, Florian Meneau, José E Krieger, Ayumi A Miyakawa.

Mitochondria are dynamic organelles that change morphology to adapt to cellular energetic demands under both physiological and stress conditions. Cardiomyopathies and neuronal disorders are associated with structure-related dysfunction in mitochondria, but three-dimensional characterizations of the organelles are still lacking. In this study, we combined high-resolution imaging and 3D electron density information provided by cryo-soft X-ray tomography to characterize mitochondria cristae morphology isolated from murine. Using the linear attenuation coefficient, the mitochondria were identified (0.247 ± 0.04 µm-1) presenting average dimensions of 0.90 ± 0.20 µm in length and 0.63 ± 0.12 µm in width. The internal mitochondria structure was successfully identified by reaching up the limit of spatial resolution of 35 nm. The internal mitochondrial membranes invagination (cristae) complexity was calculated by the mitochondrial complexity index (MCI) providing quantitative and morphological information of mitochondria larger than 0.90 mm in length. The segmentation to visualize the cristae invaginations into the mitochondrial matrix was possible in mitochondria with MCI ≥ 7. Altogether, we demonstrated that the MCI is a valuable quantitative morphological parameter to evaluate cristae modelling and can be applied to compare healthy and disease state associated to mitochondria morphology.

DOI: https://doi.org/10.1038/s41598-020-78150-3
EMBO Rep. 2020 Dec 03. e51830

Supercomplex formation boosts respiration.

Fabian den Brave, Thomas Becker.

Mitochondrial respiratory chain complexes associate in supercomplexes, but the physiological role of these assemblies remains controversial. Recent studies in EMBO Reports reveal that supercomplexes promote metabolic fitness. Berndtsson et al (2020) demonstrate that supercomplex formation enhances electron transport by reducing the distance for diffusion of cytochrome c between cytochrome bc1 complex and cytochrome c oxidase and thereby increases competitive fitness in yeast. Similarly, Garcia-Poyatos et al (2020) report that zebrafish lacking the supercomplex assembly factor SCAF1 display a reduced growth and decreased female fertility.

DOI: https://doi.org/10.15252/embr.202051830
Metabolomics. 2020 Nov 29. 16(12): 125

Mapping choline metabolites in normal and transformed cells.

Irena Roci, Jeramie D Watrous, Kim A Lagerborg, Mohit Jain, Roland Nilsson.

  INTRODUCTION: Choline is an essential human nutrient that is particular important for proliferating cells, and altered choline metabolism has been associated with cancer transformation. Yet, the various metabolic fates of choline in proliferating cells have not been investigated systematically.OBJECTIVES: This study aims to map the metabolic products of choline in normal and cancerous proliferating cells.
METHODS: We performed 13C-choline tracing followed by liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis of metabolic products in normal and in vitro-transformed (tumor-forming) epithelial cells, and also in tumor-derived cancer cell lines. Selected metabolites were quantified by internal standards.
RESULTS: Untargeted analysis revealed 121 LCMS peaks that were 13C-labeled from choline, including various phospholipid species, but also previously unknown products such as monomethyl- and dimethyl-ethanolamines. Interestingly, we observed formation of betaine from choline specifically in tumor-derived cells. Expression of choline dehydrogenase (CHDH), which catalyzes the first step of betaine synthesis, correlated with betaine synthesis across the cell lines studied. RNAi silencing of CHDH did not affect cell proliferation, although we observed an increased fraction of G2M phase cells with some RNAi sequences, suggesting that CHDH and its product betaine may play a role in cell cycle progression. Betaine cell concentration was around 10 µM, arguing against an osmotic function, and was not used as a methyl donor. The function of betaine in these tumor-derived cells is presently unknown.
CONCLUSION: This study identifies novel metabolites of choline in cancer and normal cell lines, and reveals altered choline metabolism in cancer cells.

Keywords:  13C3 choline; Betaine; CHDH; Isotope tracing; Methylation

DOI:  https://doi.org/10.1007/s11306-020-01749-0
Nat Rev Drug Discov. 2020 Dec 01.

Inhibiting enolase eradicates tumours.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-020-00210-0
Nature. 2020 Dec 02.

Reversal of biological clock restores vision in old mice.

Heidi Ledford.



Keywords:  Ageing; Cell biology; Diseases; Epigenetics

DOI:  https://doi.org/10.1038/d41586-020-03403-0
Annu Rev Pathol. 2020 Dec 04.

When a House Is Not a Home: A Survey of Antimetastatic Niches and Potential Mechanisms of Disseminated Tumor Cell Suppression.

Sarah B Crist, Cyrus M Ghajar.

Over the last four decades, the cancer biology field has concentrated on cellular and microenvironmental drivers of metastasis. Despite this focus, mortality rates upon diagnosis of metastatic disease remain essentially unchanged. Would a small change in perspective help? Knowing what constitutes an inhospitable, rather than hospitable, microenvironment could provide the inspiration necessary to develop better therapies and preventative strategies. In this review, we canvas the literature for hints about what characteristics three common antimetastatic niches-skeletal muscle, thyroid, and spleen-have in common. We posit that thorough molecular and mechanistic characterization of antimetastatic tissues may inspire reimagined therapies that inhibit metastatic development and/or progression in an enduring manner. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 25, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathmechdis-012419-032647
Semin Cancer Biol. 2020 Dec 01. pii: S1044-579X(20)30254-6. [Epub ahead of print]

Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy.

K J Pienta, E U Hammarlund, R H Austin, R Axelrod, J S Brown, S R Amend.

  Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.

Keywords:  convergent evolution; lethal cancer; polyploid giant cancer cells; therapeutic resistance; whole genome doubling

DOI:  https://doi.org/10.1016/j.semcancer.2020.11.016
Nature. 2020 Dec 04.

How to write a superb literature review.

Andy Tay.



Keywords:  Careers; Publishing; Research management

DOI:  https://doi.org/10.1038/d41586-020-03422-x
Nat Commun. 2020 12 03. 11(1): 6182

DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity.

Xiaona Sun, Ting Liu, Jun Zhao, Hansong Xia, Jun Xie, Yu Guo, Li Zhong, Mi Li, Qing Yang, Cheng Peng, Isabelle Rouvet, Alexandre Belot, Hong-Bing Shu, Pinghui Feng, Junjie Zhang.

Upon sensing cytosolic DNA, the enzyme cGAS induces innate immune responses that underpin anti-microbial defenses and certain autoimmune diseases. Missense mutations of PRKDC encoding the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) are associated with autoimmune diseases, yet how DNA-PK deficiency leads to increased immune responses remains poorly understood. In this study, we report that DNA-PK phosphorylates cGAS and suppresses its enzymatic activity. DNA-PK deficiency reduces cGAS phosphorylation and promotes antiviral innate immune responses, thereby potently restricting viral replication. Moreover, cells isolated from DNA-PKcs-deficient mice or patients carrying PRKDC missense mutations exhibit an inflammatory gene expression signature. This study provides a rational explanation for the autoimmunity of patients with missense mutations of PRKDC, and suggests that cGAS-mediated immune signaling is a potential target for therapeutic interventions.

DOI: https://doi.org/10.1038/s41467-020-19941-0
Nature. 2020 Dec;588(7836): 124-129

Reprogramming to recover youthful epigenetic information and restore vision.

Yuancheng Lu, Benedikt Brommer, Xiao Tian, Anitha Krishnan, Margarita Meer, Chen Wang, Daniel L Vera, Qiurui Zeng, Doudou Yu, Michael S Bonkowski, Jae-Hyun Yang, Songlin Zhou, Emma M Hoffmann, Margarete M Karg, Michael B Schultz, Alice E Kane, Noah Davidsohn, Ekaterina Korobkina, Karolina Chwalek, Luis A Rajman, George M Church, Konrad Hochedlinger, Vadim N Gladyshev, Steve Horvath, Morgan E Levine, Meredith S Gregory-Ksander, Bruce R Ksander, Zhigang He, David A Sinclair.

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1-3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5-7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.

DOI: https://doi.org/10.1038/s41586-020-2975-4