bims-camemi 2023-02-12 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023–02–12
48 papers selected by
Christian Frezza, Universität zu Köln

Allosteric regulation of CAD modulates de novo pyrimidine synthesis during the cell cycle.
Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
Oncogenic IDH1 Mutation Imparts Therapeutically Targetable Metabolic Dysfunction in Multiple Tumor Types.
Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.
Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.
L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.
Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle.
Cuproptosis: p53-regulated metabolic cell death?
The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
Contribution of NRF2 to sulfur metabolism and mitochondrial activity.
Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.
ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling.
Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation.
Salty Treg cells get out of balance.
Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1.
Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.
Oxidized mitochondrial DNA: a protective signal gone awry.
Bilateral JNK activation is a hallmark of interface surveillance and promotes elimination of aberrant cells.
DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.
How and why the circadian clock regulates proliferation of adult epithelial stem cells.
The Journey of Mitochondrial Protein Import and the Roadmap to Follow.
Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs.
Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.
Mining microbial metabolism.
Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.
Metabolic individuality: Limitations, challenges, and potential for clinical utility.
CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons.
Islet microexons: tiny new players in glucose homeostasis.
13C-Metabolic flux analysis of 3T3-L1 adipocytes illuminates its core metabolism under hypoxia.
A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment.
Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation.
Control of immune cell function by the unfolded protein response.
The cell cycle loops UTP around CAD.
Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.
Organ Protection by Caloric Restriction Depends on Activation of the de novo NAD+ Synthesis Pathway.
Glutathionylation of Pyruvate Dehydrogenase Complex E2 Protein During Acute Inflammation Is Magnified By Mitochondrial Oxidative Stress, Enhancing Cell Death.
Characterization of Chlorogenic Acid as a Two-Photon Fluorogenic Probe that Regulates Glycolysis in Tumor Cells under Hypoxia.
GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT.
Gaucher disease protects against tuberculosis.
Mutated HRAS activates YAP1-AXL signaling to drive metastasis of head and neck cancer.
Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death.
Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer.
EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer.
Metabolic flexibility in ccRCC.
Ischemia promotes acyl-CoAs dephosphorylation and propionyl-CoA accumulation.
Spatially non-uniform condensates emerge from dynamically arrested phase separation.
Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice.

Nat Metab. 2023 Feb 06.

Allosteric regulation of CAD modulates de novo pyrimidine synthesis during the cell cycle.

Jong Shin, Hannan Mir, Maaz A Khurram, Kenji M Fujihara, Brian D Dynlacht, Timothy J Cardozo, Richard Possemato.

Metabolism is a fundamental cellular process that is coordinated with cell cycle progression. Despite this association, a mechanistic understanding of cell cycle phase-dependent metabolic pathway regulation remains elusive. Here we report the mechanism by which human de novo pyrimidine biosynthesis is allosterically regulated during the cell cycle. Combining traditional synchronization methods and metabolomics, we characterize metabolites by their accumulation pattern during cell cycle phases and identify cell cycle phase-dependent regulation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase (CAD), the first, rate-limiting enzyme in de novo pyrimidine biosynthesis. Through systematic mutational scanning and structural modelling, we find allostery as a major regulatory mechanism that controls the activity change of CAD during the cell cycle. Specifically, we report evidence of two Animalia-specific loops in the CAD allosteric domain that involve sensing and binding of uridine 5'-triphosphate, a CAD allosteric inhibitor. Based on homology with a mitochondrial carbamoyl-phosphate synthetase homologue, we identify a critical role for a signal transmission loop in regulating the formation of a substrate channel, thereby controlling CAD activity.

DOI: https://doi.org/10.1038/s42255-023-00735-9
Nature. 2023 Feb 08.

Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.

Joe Nassour, Lucia Gutierrez Aguiar, Adriana Correia, Tobias T Schmidt, Laura Mainz, Sara Przetocka, Candy Haggblom, Nimesha Tadepalle, April Williams, Maxim N Shokhirev, Semih C Akincilar, Vinay Tergaonkar, Gerald S Shadel, Jan Karlseder.

Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.

DOI: https://doi.org/10.1038/s41586-023-05710-8
Cancer Discov. 2023 Feb 06. 13(2): 266-268

Oncogenic IDH1 Mutation Imparts Therapeutically Targetable Metabolic Dysfunction in Multiple Tumor Types.

Troy M Robinson, Ross L Levine.

SUMMARY: In this issue of Cancer Discovery, Thomas and colleagues leverage mass spectrometry metabolomics, stable isotope labeling, and functional studies to explore metabolic vulnerabilities in cancers harboring mutations in isocitrate dehydrogenase (IDH). The authors present compelling data to support the claim that dysregulated lipid synthesis underpins a synthetic lethal target in cancers with IDH1, but not IDH2, mutations. See related article by Thomas et al., p. 496 (9).

DOI: https://doi.org/10.1158/2159-8290.CD-22-1325
Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00003-7. [Epub ahead of print]35(2): 345-360.e7

Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.

Joonho Suh, Na-Kyung Kim, Wonn Shim, Seung-Hoon Lee, Hyo-Jeong Kim, Eunyoung Moon, Hiromi Sesaki, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee.

  Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.

Keywords:  FIS1; M1; OPA1; donut mitochondria; mitochondria; mitochondrial secretion; mitochondrial transplantation; mitochondrial-derived vesicles; osteoblasts; osteogenesis

DOI:  https://doi.org/10.1016/j.cmet.2023.01.003
Oncogene. 2023 Feb 04.

Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.

Zeribe Chike Nwosu, Mun Gu Song, Marina Pasca di Magliano, Costas A Lyssiotis, Sung Eun Kim.

Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.

DOI: https://doi.org/10.1038/s41388-023-02593-x
Nat Cell Biol. 2023 Feb 06.

Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.

Xiaoguang Liu, Litong Nie, Yilei Zhang, Yuelong Yan, Chao Wang, Medina Colic, Kellen Olszewski, Amber Horbath, Xiong Chen, Guang Lei, Chao Mao, Shiqi Wu, Li Zhuang, Masha V Poyurovsky, M James You, Traver Hart, Daniel D Billadeau, Junjie Chen, Boyi Gan.

SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.

DOI: https://doi.org/10.1038/s41556-023-01091-2
EMBO J. 2023 Feb 06. e112647

L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.

Mingyue Xu, Ye Guo, Min Wang, Xing Luo, Xuning Shen, Zhimin Li, Lei Wang, Weixiang Guo.

  Neurogenesis in the developing and adult brain is intimately linked to remodeling of cellular metabolism. However, it is still unclear how distinct metabolic programs and energy sources govern neural stem cell (NSC) behavior and subsequent neuronal differentiation. Here, we found that adult mice lacking the mitochondrial urea metabolism enzyme, Arginase-II (Arg-II), exhibited NSC overactivation, thereby leading to accelerated NSC pool depletion and decreased hippocampal neurogenesis over time. Mechanistically, Arg-II deficiency resulted in elevated L-arginine levels and induction of a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) caused by impaired attachment of hexokinase-I to mitochondria. Notably, selective inhibition of OXPHOS ameliorated NSC overactivation and restored abnormal neurogenesis in Arg-II deficient mice. Therefore, Arg-II-mediated intracellular L-arginine homeostasis directly influences the metabolic fitness of neural stem cells that is essential to maintain neurogenesis with age.

Keywords:  Adult neurogenesis; Arginase-II; Hexokinase; L-arginine; NSC pool

DOI:  https://doi.org/10.15252/embj.2022112647
Nat Commun. 2023 Feb 06. 14(1): 602

Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle.

Caterina Marchioretti, Giulia Zanetti, Marco Pirazzini, Gaia Gherardi, Leonardo Nogara, Roberta Andreotti, Paolo Martini, Lorenzo Marcucci, Marta Canato, Samir R Nath, Emanuela Zuccaro, Mathilde Chivet, Cristina Mammucari, Marco Pacifici, Anna Raffaello, Rosario Rizzuto, Andrea Mattarei, Maria A Desbats, Leonardo Salviati, Aram Megighian, Gianni Sorarù, Elena Pegoraro, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Chiara Romualdi, Andrew P Lieberman, Gopal J Babu, Marco Sandri, Bert Blaauw, Manuela Basso, Maria Pennuto.

Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure.

DOI: https://doi.org/10.1038/s41467-023-36185-w
Cell Death Differ. 2023 Feb 08.

Cuproptosis: p53-regulated metabolic cell death?

Chen Xiong, Hong Ling, Qian Hao, Xiang Zhou.

Cuproptosis is a novel type of copper-induced cell death that primarily occurs in cells that utilize oxidative phosphorylation as the main metabolic pathway to produce energy. Copper directly associates with the lipoylated proteins of the tricarboxylic acid cycle, leading to the disulfide-bond-dependent aggregation of these lipoylated proteins, destabilization of the iron-sulfur cluster proteins, and consequent proteotoxic stress. Cancer cells prefer glycolysis (Warburg effect) to oxidative phosphorylation for producing intermediate metabolites and energy, thereby achieving resistance to cuproptosis. Interestingly, the tumor suppressor p53 is a crucial metabolic regulator that inhibits glycolysis and drives a metabolic switch towards oxidative phosphorylation in cancer cells. Additionally, p53 regulates the biogenesis of iron-sulfur clusters and the copper chelator glutathione, which are two critical components of the cuproptotic pathway, suggesting that this tumor suppressor might play a role in cuproptosis. Furthermore, the possible roles of mutant p53 in regulating cuproptosis are discussed. In this essay, we review the recent progress in the understanding of the mechanism underlying cuproptosis, revisit the roles of p53 in metabolic regulation and iron-sulfur cluster and glutathione biosynthesis, and propose several potential mechanisms for wild-type and mutant p53-mediated cuproptosis regulation.

DOI: https://doi.org/10.1038/s41418-023-01125-0
Nat Commun. 2023 Feb 06. 14(1): 638

The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.

Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman.

The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.

DOI: https://doi.org/10.1038/s41467-023-36298-2
Redox Biol. 2023 Feb 02. pii: S2213-2317(23)00025-3. [Epub ahead of print]60 102624

Contribution of NRF2 to sulfur metabolism and mitochondrial activity.

Md Morshedul Alam, Akihiro Kishino, Eunkyu Sung, Hiroki Sekine, Takaaki Abe, Shohei Murakami, Takaaki Akaike, Hozumi Motohashi.

  NF-E2-related factor 2 (NRF2) plays a crucial role in the maintenance of cellular homeostasis by regulating various enzymes and proteins that are involved in the redox reactions utilizing sulfur. While substantial impacts of NRF2 on mitochondrial activity have been described, the precise mechanism by which NRF2 regulates mitochondrial function is still not fully understood. Here, we demonstrated that NRF2 increased intracellular persulfides by upregulating the cystine transporter xCT encoded by Slc7a11, a well-known NRF2 target gene. Persulfides have been shown to play an important role in mitochondrial function. Supplementation with glutathione trisulfide (GSSSG), which is a form of persulfide, elevated the mitochondrial membrane potential (MMP), increased the oxygen consumption rate (OCR) and promoted ATP production. Persulfide-mediated mitochondrial activation was shown to require the mitochondrial sulfur oxidation pathway, especially sulfide quinone oxidoreductase (SQOR). Consistently, NRF2-mediated mitochondrial activation was also dependent on SQOR activity. This study clarified that the facilitation of persulfide production and sulfur metabolism in mitochondria by increasing cysteine availability is one of the mechanisms for NRF2-dependent mitochondrial activation.

Keywords:  Cysteine; Cystine; Mitochondria; Mitochondrial membrane potential; Persulfide; xCT

DOI:  https://doi.org/10.1016/j.redox.2023.102624
bioRxiv. 2023 Jan 24. pii: 2023.01.24.525419. [Epub ahead of print]

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.

Andrew R Patterson, Gabriel A Needle, Ayaka Sugiura, Channing Chi, KayLee K Steiner, Emilie L Fisher, Gabriella L Robertson, Caroline Bodnya, Janet G Markle, Vivian Gama, Jeffrey C Rathmell.

Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1 , are critical for T cell expansion and function. Interestingly, Gfpt1 -deficient T H 1 cells were more affected than T H 17 cells, which had increased Nagk for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor Bcl11b promotes CD4 + T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders.
HIGHLIGHTS: Inborn errors of immunity and metabolism have greater overlap than previously known Gfpt1 deficiency causes an IEM but also selectively regulates T cell subset fate Loss of Bcl11b causes a T cell deficiency IEI but also harms mitochondrial function Many IEM may have immune defects and IEI may be driven by metabolic mechanisms.

DOI: https://doi.org/10.1101/2023.01.24.525419
Nat Commun. 2023 Feb 04. 14(1): 611

ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling.

Matteo Gentili, Bingxu Liu, Malvina Papanastasiou, Deborah Dele-Oni, Marc A Schwartz, Rebecca J Carlson, Aziz M Al'Khafaji, Karsten Krug, Adam Brown, John G Doench, Steven A Carr, Nir Hacohen.

Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling.

DOI: https://doi.org/10.1038/s41467-023-36132-9
Elife. 2023 Feb 07. pii: e84319. [Epub ahead of print]12

Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation.

Marco Caligaris, Raffaele Nicastro, Zehan Hu, Farida Tripodi, Johannes Erwin Hummel, Benjamin Pillet, Marie-Anne Deprez, Joris Winderickx, Sabine Rospert, Paola Coccetti, Jörn Dengjel, Claudio De Virgilio.

  The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energy levels activate TORC1 to promote growth. Both in mammals and lower eukaryotes such as yeast, the AMPK and TORC1 pathways are wired to each other at different levels, which ensures homeostatic control of growth and metabolism. In this context, a previous study (Hughes Hallet et. al, 2015) reported that AMPK in yeast, i.e. Snf1, prevents the transient TORC1 reactivation during the early phase following acute glucose starvation, but the underlying mechanism has remained elusive. Using a combination of unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, and physiological experiments, we show here that Snf1 temporally maintains TORC1 inactive in glucose-starved cells primarily through the TORC1-regulatory protein Pib2. Our data, therefore, extend the function of Pib2 to a hub that integrates both glucose and, as reported earlier, glutamine signals to control TORC1. We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region and thereby antagonizes the phosphorylation of a C-terminal TORC1-target residue within Sch9 itself that is critical for its activity. The consequences of Snf1-mediated phosphorylation of Pib2 and Sch9 are physiologically additive and sufficient to explain the role of Snf1 in short-term inhibition of TORC1 in acutely glucose-starved cells.

Keywords:  S. cerevisiae; biochemistry; cell biology; chemical biology

DOI:  https://doi.org/10.7554/eLife.84319
Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00008-6. [Epub ahead of print]35(2): 228-230

Salty Treg cells get out of balance.

Iosif Papafragkos, Panayotis Verginis.

Although metabolic rewiring of Treg cells constitutes a hallmark in autoimmune diseases, extrinsic and intrinsic mechanisms that imprint on this re-programming remain poorly understood. In this issue of Cell Metabolism, Côrte-Real and colleagues demonstrate that high salt exposure disturbs the mitochondrial respiration in Treg cells, promoting a pro-inflammatory phenotype, loss of function, and associated breakdown of self-tolerance.

DOI: https://doi.org/10.1016/j.cmet.2023.01.008
Oncogene. 2023 Feb 09.

Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1.

Linmeng Han, Chunyu Zhang, Danni Wang, Jiaqi Zhang, Qiqi Tang, Mulin Jun Li, Michael N Sack, Lingdi Wang, Lu Zhu.

Metabolic reprogram is crucial to support cancer cell growth and movement as well as determine cell fate. Mitochondrial protein acetylation regulates mitochondrial metabolism, which is relevant to cancer cell migration and invasion. The functional role of mitochondrial protein acetylation on cancer cell migration remains unclear. General control of amino acid synthesis 5 like-1(GCN5L1), as the regulator of mitochondrial protein acetylation, functions on metabolic reprogramming in mouse livers. In this study, we find that GCN5L1 expression is significantly decreased in metastatic HCC tissues. Loss of GCN5L1 promotes reactive oxygen species (ROS) generation through enhanced fatty acid oxidation (FAO), followed by activation of cellular ERK and DRP1 to promote mitochondrial fission and epithelia to mesenchymal transition (EMT) to boost cell migration. Moreover, palmitate and carnitine-stimulated FAO promotes mitochondrial fission and EMT gene expression to activate HCC cell migration. On the other hand, increased cellular acetyl-CoA level, the product of FAO, enhances HCC cell migration. Taken together, our finding uncovers the metastasis suppressor role as well as the underlying mechanism of GCN5L1 in HCC and also provides evidence of FAO retrograde control of HCC metastasis.

DOI: https://doi.org/10.1038/s41388-023-02621-w
Int J Mol Sci. 2023 Jan 19. pii: 1969. [Epub ahead of print]24(3):

Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.

Marco D'Amato, Francesca Morra, Ivano Di Meo, Valeria Tiranti.

  Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.

Keywords:  mitochondria; mitochondrial diseases; mitochondrial dysfunction; mitochondrial medicine; mitochondrial transplantation

DOI:  https://doi.org/10.3390/ijms24031969
Trends Immunol. 2023 Feb 02. pii: S1471-4906(23)00017-0. [Epub ahead of print]

Oxidized mitochondrial DNA: a protective signal gone awry.

Hongxu Xian, Michael Karin.

  Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1β, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.

Keywords:  NLRP3 inflammasome; Ox-mtDNA; autoimmunity; cGAS–STING; cell-free DNA; immunopathology; inflammation; stressed mitochondria

DOI:  https://doi.org/10.1016/j.it.2023.01.006
Elife. 2023 Feb 06. pii: e80809. [Epub ahead of print]12

Bilateral JNK activation is a hallmark of interface surveillance and promotes elimination of aberrant cells.

Deepti Prasad, Katharina Illek, Friedericke Fischer, Katrin Holstein, Anne-Kathrin Classen.

  Tissue-intrinsic defense mechanisms eliminate aberrant cells from epithelia and thereby maintain the health of developing tissues or adult organisms. 'Interface surveillance' comprises one such distinct mechanism that specifically guards against aberrant cells which undergo inappropriate cell fate and differentiation programs. The cellular mechanisms which facilitate detection and elimination of these aberrant cells are currently unknown. We find that in Drosophila imaginal discs, clones of cells with inappropriate activation of cell fate programs induce bilateral JNK activation at clonal interfaces, where wild type and aberrant cells make contact. JNK activation is required to drive apoptotic elimination of interface cells. Importantly, JNK activity and apoptosis are highest in interface cells within small aberrant clones, which likely supports the successful elimination of aberrant cells when they arise. Our findings are consistent with a model where clone size affects the topology of interface contacts and thereby the strength of JNK activation in wild type and aberrant interface cells. Bilateral JNK activation is unique to 'interface surveillance' and is not observed in other tissue-intrinsic defense mechanisms, such as classical 'cell-cell competition'. Thus, bilateral JNK interface signaling provides an independent tissue-level mechanism to eliminate cells with inappropriate developmental fate but normal cellular fitness. Finally, oncogenic Ras-expressing clones activate 'interface surveillance' but evade elimination by bilateral JNK activation. Combined, our work establishes bilateral JNK interface signaling and interface apoptosis as a new hallmark of interface surveillance and highlights how oncogenic mutations evade tumor suppressor function encoded by this tissue-intrinsic surveillance system.

Keywords:  D. melanogaster; JNK; apoptosis; cancer biology; cell competition; cell elimination; developmental biology; epithelial cells; interface contractility

DOI:  https://doi.org/10.7554/eLife.80809
J Cell Sci. 2023 Feb 01. pii: jcs260370. [Epub ahead of print]136(3):

DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.

Gabriella L Robertson, Stellan Riffle, Mira Patel, Caroline Bodnya, Andrea Marshall, Heather K Beasley, Edgar Garza-Lopez, Jianqiang Shao, Zer Vue, Antentor Hinton, Maria S Stoll, Sholto de Wet, Rensu P Theart, Ram Prosad Chakrabarty, Ben Loos, Navdeep S Chandel, Jason A Mears, Vivian Gama.

  Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) - a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.

Keywords:  Cristae; DRP1; Fibroblast; Glycolysis; Mitochondria; Oxidative phosphorylation; Peroxisome

DOI:  https://doi.org/10.1242/jcs.260370
Stem Cells. 2023 Feb 06. pii: sxad013. [Epub ahead of print]

How and why the circadian clock regulates proliferation of adult epithelial stem cells.

Bogi Andersen, Junyan Duan, Satya Swaroop Karri.

First described in the early 20 th century, diurnal oscillations in stem cell proliferation exist in multiple internal epithelia, including in the gastrointestinal track, and in the epidermis. In the mouse epidermis, 3- to 4-fold more stem cells are in S-phase during the night than during the day. Work that is more recent showed that an intact circadian clock intrinsic to keratinocytes is required for these oscillations in epidermal stem cell proliferation. The circadian clock also regulates DNA excision repair and DNA-damage in epidermal stem cells in response to ultraviolet B radiation. During skin inflammation, epidermal stem cell proliferation is increased and diurnal oscillations are suspended. Here we discuss possible reasons for the evolution of this stem cell phenomenon. We argue that the circadian clock coordinates intermediary metabolism and the cell cycle in epidermal stem cells to minimize accumulation of DNA damage from metabolism-generated reactive oxygen species. Circadian disruption, common in modern society, leads to asynchrony between metabolism and the cell cycle, and we speculate this will lead to oxidative DNA damage, dysfunction of epidermal stem cells, and skin aging.

DOI: https://doi.org/10.1093/stmcls/sxad013
Int J Mol Sci. 2023 Jan 27. pii: 2479. [Epub ahead of print]24(3):

The Journey of Mitochondrial Protein Import and the Roadmap to Follow.

Mary Oluwadamilola Haastrup, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta.

  Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.

Keywords:  diseases; mitochondria; mitochondrial protein import machineries; mitochondrial unfolded protein response; proteins

DOI:  https://doi.org/10.3390/ijms24032479
Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00009-8. [Epub ahead of print]35(2): 299-315.e8

Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs.

Beatriz F Côrte-Real, Ibrahim Hamad, Rebeca Arroyo Hornero, Sabrina Geisberger, Joris Roels, Lauren Van Zeebroeck, Aleksandra Dyczko, Marike W van Gisbergen, Henry Kurniawan, Allon Wagner, Nir Yosef, Susanne N Y Weiss, Klaus G Schmetterer, Agnes Schröder, Luka Krampert, Stefanie Haase, Hendrik Bartolomaeus, Niels Hellings, Yvan Saeys, Ludwig J Dubois, Dirk Brenner, Stefan Kempa, David A Hafler, Johannes Stegbauer, Ralf A Linker, Jonathan Jantsch, Dominik N Müller, Markus Kleinewietfeld.

  FOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.

Keywords:  FOXP3; autoimmunity; high salt; mitochondrial respiration; regulatory T cells

DOI:  https://doi.org/10.1016/j.cmet.2023.01.009
Curr Opin Neurobiol. 2023 Feb 06. pii: S0959-4388(23)00009-0. [Epub ahead of print]79 102684

Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.

Robert W Mahley.

Apolipoprotein (apo) E4 sets the stage for neuropathology in Alzheimer's disease (AD) by causing mitochondrial dysfunction and altering mitochondria-associated membranes. Contact and apposition of mitochondrial-endoplasmic reticulum membranes are enhanced in brain cells in AD and associated with increases in tethering and spacing proteins that modulate many cellular processes. Contact site protein levels are higher in apoE4 cells. In apoE4 neurons, the NAD+/NADH ratio is lowered, reactive oxygen species are increased, and NAD/NADH pathway components and redox proteins are decreased. Oxidative phosphorylation is impaired and reserve ATP generation capacity is lacking. ApoE4 neurons have ∼50% fewer respiratory complex subunits (e.g., ATP synthase) and may increase translocase levels of the outer and inner mitochondrial membranes to facilitate delivery of nucleus-encoded complex subunits. Respiratory complex assembly relies on mitochondrial cristae organizing system subunits that are altered in apoE4 cells, and apoE4 increases mitochondrial proteases that control respiratory subunit composition for complex assembly.

DOI: https://doi.org/10.1016/j.conb.2023.102684
Nat Chem Biol. 2023 Feb 06.

Mining microbial metabolism.

Yinjie J Tang, Tae Seok Moon.

DOI: https://doi.org/10.1038/s41589-023-01257-x
Leukemia. 2023 Feb 04.

Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.

Clement Larrue, Sarah Mouche, Shan Lin, Federico Simonetta, Nastassja K Scheidegger, Laury Poulain, Rudy Birsen, Jean-Emmanuel Sarry, Kimberly Stegmaier, Jerome Tamburini.

Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.

DOI: https://doi.org/10.1038/s41375-023-01835-x
Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00007-4. [Epub ahead of print]35(2): 233-235

Metabolic individuality: Limitations, challenges, and potential for clinical utility.

Sarah H Elsea, Jennifer E Posey.

In Nature Medicine, Surendran and colleagues recently reported the analysis of human plasma metabolomic data for 913 metabolites in ∼20,000 individuals, identifying 2,599 metabolite-genetic variant associations and >400 metabolite signatures comprised of jointly regulated metabolites. This extensive atlas of variant-metabolite relationships reveals novel genomic mechanisms driving metabolic phenotypes.

DOI: https://doi.org/10.1016/j.cmet.2023.01.007
Nat Commun. 2023 Feb 08. 14(1): 692

CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons.

Gong-Her Wu, Charlene Smith-Geater, Jesús G Galaz-Montoya, Yingli Gu, Sanket R Gupte, Ranen Aviner, Patrick G Mitchell, Joy Hsu, Ricardo Miramontes, Keona Q Wang, Nicolette R Geller, Cathy Hou, Cristina Danita, Lydia-Marie Joubert, Michael F Schmid, Serena Yeung, Judith Frydman, William Mobley, Chengbiao Wu, Leslie M Thompson, Wah Chiu.

Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

DOI: https://doi.org/10.1038/s41467-023-36096-w
Nat Metab. 2023 Feb 09.

Islet microexons: tiny new players in glucose homeostasis.

DOI: https://doi.org/10.1038/s42255-023-00739-5
Metab Eng. 2023 Feb 07. pii: S1096-7176(23)00022-8. [Epub ahead of print]

13C-Metabolic flux analysis of 3T3-L1 adipocytes illuminates its core metabolism under hypoxia.

Eleanor H Oates, Maciek R Antoniewicz.

  Hypoxia has been identified as a major factor in the pathogenesis of adipose tissue inflammation, which is a hallmark of obesity and obesity-linked type 2 diabetes mellitus. In this study, we have investigated the impact of hypoxia (1% oxygen) on the physiology and metabolism of 3T3-L1 adipocytes, a widely used cell culture model of adipose. Specifically, we applied parallel labeling experiments, isotopomer spectral analysis, and 13C-metabolic flux analysis to quantify the impact of hypoxia on adipogenesis, de novo lipogenesis and metabolic flux reprogramming in adipocytes. We found that 3T3-L1 cells can successfully differentiate into lipid-accumulating adipocytes under hypoxia, although the production of lipids was reduced by about 40%. Quantitative flux analysis demonstrated that short-term (1 day) and long-term (7 days) exposure to hypoxia resulted in similar reprogramming of cellular metabolism. Overall, we found that hypoxia: 1) reduced redox and energy generation by more than 2-fold and altered the patterns of metabolic pathway contributions to production and consumption of energy and redox cofactors; 2) redirected glucose metabolism from pentose phosphate pathway and citric acid cycle to lactate production; 3) rewired glutamine metabolism, from net glutamine production to net glutamine catabolism; 4) suppressed branched chain amino acid consumption; and 5) reduced biosynthesis of odd-chain fatty acids and mono-unsaturated fatty acids, while synthesis of saturated even-chain fatty acids was not affected. Together, these results highlight the profound impact of extracellular microenvironment on adipocyte metabolic activity and function.

Keywords:  3T3-L1 cells; Adipocytes; Differentiation; Hypoxia; Metabolism; de novo lipogenesis

DOI:  https://doi.org/10.1016/j.ymben.2023.02.002
J Theor Biol. 2023 Feb 03. pii: S0022-5193(23)00030-9. [Epub ahead of print] 111434

A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment.

Pierre Jacquet, Angélique Stéphanou.

  Cancer cells metabolism focuses the interest of the cancer research community. Although this process is intensely studied experimentally, there are very few theoretical models that address this issue. One of the main reasons is the extraordinary complexity of the metabolism that involves numerous interdependent regulatory networks which makes the computational recreation of this complexity illusory. In this study we propose a reduced model of the metabolism which focuses on the interrelation of the three main energy metabolites which are oxygen, glucose and lactate in order to better understand the dynamics of the core system of the glycolysis-OXPHOS relationship. So simple as it is, the model highlights the main rules allowing the cell to dynamically adapt its metabolism to its changing environment. It also makes it possible to address this impact at the tissue scale. The simulations carried out in a spheroid show non-trivial spatial heterogeneity of energy metabolism. It further suggests that the metabolic features that are commonly attributed to cancer cells are not necessarily due to an intrinsic abnormality of the cells. They can emerge spontaneously due to the deregulated over-acidic environment.

Keywords:  Acidity; Energetic needs; Pyruvate-lactate; Theoretical model; Warburg effect

DOI:  https://doi.org/10.1016/j.jtbi.2023.111434
Nat Commun. 2023 Feb 07. 14(1): 660

Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation.

Mutian Jia, Yuanyuan Wang, Jie Wang, Danhui Qin, Mengge Wang, Li Chai, Yue Fu, Chunyuan Zhao, Chengjiang Gao, Jihui Jia, Wei Zhao.

Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of STING-induced interferon (IFN) responses. Thus, the mechanisms that ensure the beneficial effects of STING activation are of particular importance. Herein, we show that myristic acid, a type of long-chain saturated fatty acid (SFA), specifically attenuates cGAS-STING-induced IFN responses in macrophages, while enhancing STING-dependent autophagy. Myristic acid inhibits HSV-1 infection-induced innate antiviral immune responses and promotes HSV-1 replication in mice in vivo. Mechanistically, myristic acid enhances N-myristoylation of ARF1, a master regulator that controls STING membrane trafficking. Consequently, myristic acid facilitates STING activation-triggered autophagy degradation of the STING complex. Thus, our work identifies myristic acid as a metabolic checkpoint that contributes to immune homeostasis by balancing STING-dependent autophagy and IFN responses. This suggests that myristic acid and N-myristoylation are promising targets for the treatment of diseases caused by aberrant STING activation.

DOI: https://doi.org/10.1038/s41467-023-36332-3
Nat Rev Immunol. 2023 Feb 08.

Control of immune cell function by the unfolded protein response.

Giusy Di Conza, Ping-Chih Ho, Juan R Cubillos-Ruiz, Stanley Ching-Cheng Huang.

Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes orchestrated by the endoplasmic reticulum. Importantly, diverse extracellular and intracellular conditions can compromise the protein-handling capacity of this organelle, inducing a state of 'endoplasmic reticulum stress' that activates the unfolded protein response (UPR). Emerging evidence shows that physiological or pathological activation of the UPR can have effects on immune cell survival, metabolism, function and fate. In this Review, we discuss the canonical role of the adaptive UPR in immune cells and how dysregulation of this pathway in leukocytes contributes to diverse pathologies such as cancer, autoimmunity and metabolic disorders. Furthermore, we provide an overview as to how pharmacological approaches that modulate the UPR could be harnessed to control or activate immune cell function in disease.

DOI: https://doi.org/10.1038/s41577-023-00838-0
Nat Metab. 2023 Feb 06.

The cell cycle loops UTP around CAD.

Umakant Sahu, Issam Ben-Sahra.

DOI: https://doi.org/10.1038/s42255-023-00737-7
Int J Mol Sci. 2023 Jan 25. pii: 2337. [Epub ahead of print]24(3):

Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.

Francesco Pacifico, Antonio Leonardi, Elvira Crescenzi.

  In this review we focus on the role of glutamine in control of cancer stem cell (CSC) fate. We first provide an overview of glutamine metabolism, and then summarize relevant studies investigating how glutamine metabolism modulates the CSC compartment, concentrating on solid tumors. We schematically describe how glutamine in CSC contributes to several metabolic pathways, such as redox metabolic pathways, ATP production, non-essential aminoacids and nucleotides biosynthesis, and ammonia production. Furthermore, we show that glutamine metabolism is a key regulator of epigenetic modifications in CSC. Finally, we briefly discuss how cancer-associated fibroblasts, adipocytes, and senescent cells in the tumor microenvironment may indirectly influence CSC fate by modulating glutamine availability. We aim to highlight the complexity of glutamine's role in CSC, which supports our knowledge about metabolic heterogeneity within the CSC population.

Keywords:  adipocytes; cancer stem cells; cancer-associated fibroblasts; glutamine; metabolism; senescent cells; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms24032337
J Am Soc Nephrol. 2023 Feb 09.

Organ Protection by Caloric Restriction Depends on Activation of the de novo NAD+ Synthesis Pathway.

Martin R Späth, K Johanna R Hoyer-Allo, Lisa Seufert, Martin Höhne, Christina Lucas, Theresa Bock, Lea Isermann, Susanne Brodesser, Jan-Wilm Lackmann, Katharina Kiefer, Felix C Koehler, Katrin Bohl, Michael Ignarski, Petra Schiller, Marc Johnsen, Torsten Kubacki, Franziska Grundmann, Thomas Benzing, Aleksandra Trifunovic, Marcus Krüger, Bernhard Schermer, Volker Burst, Roman-Ulrich Müller.

BACKGROUND: Clinical practice lacks strategies to treat acute kidney injury (AKI). Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown.
METHODS: CRISPR generated kynureninase (KYNU) knockout mice and comparative transcriptome, proteome, and metabolite analyses of murine kidneys (C57Bl6N wild type and KYNU-deficient) pre- and post-ischemia-reperfusion injury, in the context of CR or ad libitum diet, performed. Additionally, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation..
RESULTS: We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the impact of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans.
CONCLUSIONS: CR induces the de novo NAD+ synthesis pathway in the context of Ischemia-reperfusion injury and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

DOI: https://doi.org/10.1681/ASN.0000000000000087
bioRxiv. 2023 Jan 27. pii: 2023.01.26.525791. [Epub ahead of print]

Glutathionylation of Pyruvate Dehydrogenase Complex E2 Protein During Acute Inflammation Is Magnified By Mitochondrial Oxidative Stress, Enhancing Cell Death.

David L Long, Leslie B Poole, Charles E McCall.

Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9.5 megadalton mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, both LPS and MitoCDNB together are synergistic for PDCE2 glutathionylation, ROS production, and cell death. These results suggest that glutathionylation on PDCE2 lipoamide sulfurs is a specific modification associated with LPS and cell death which is not recapitulated by a general rise in mitochondrial ROS, but is enhanced after LPS treatment by rising oxidative stress exerted by MitoCDNB that impairs reductase systems.
Highlights: PDCE2 is oxidized and glutathionylated (-SSG) during acute inflammation in monocytesPDCE2 knockout cells exhibit decreased ROS production during acute inflammationLipopolysaccharide-induced PDCE2-SSG occurs in THP1 cells and fresh monocytesLipoamide-deficient PDCE2 exhibits lower LPS-induced PDCE2-SSG and ROS productionMitoCDNB leads to ROS production but not PDCE2-SSG, but is synergistic with LPS.

DOI: https://doi.org/10.1101/2023.01.26.525791
J Med Chem. 2023 Feb 06.

Characterization of Chlorogenic Acid as a Two-Photon Fluorogenic Probe that Regulates Glycolysis in Tumor Cells under Hypoxia.

Qinghua Wang, Qingyang Zhang, Zhihui Zhang, Ming Ji, Tingting Du, Jing Jin, Jian-Dong Jiang, Xiaoguang Chen, Hai-Yu Hu.

High levels of steady-state mitochondrial reactive oxygen species (ROS) and glycolysis are hallmarks of cancer. An improved understanding of interactions between tumor energetics and mitochondrial ROS modulation is useful for the development of new anticancer strategies. Here, we show that the natural product chlorogenic acid (CGA) specifically scavenged abnormally elevated mitochondrial O2•- and exhibited a two-photon fluorescence turn-on response to tumor cells under hypoxia and tumor tissues in vivo. Furthermore, we illustrated that CGA treatment reduced O2•- levels in cells, hampered activation of AMP-activated protein kinase (AMPK), and shifted metabolism from glycolysis to oxidative phosphorylation (OXPHOS), resulting in inhibition of tumor growth under hypoxia. This study demonstrates an efficient two-photon fluorescent tool for real-time assessment of mitochondrial O2•- and a clear link between reducing intracellular ROS levels by CGA treatments and regulating metabolism, as well as undeniably helpful insights for the development of new anticancer strategies.

DOI: https://doi.org/10.1021/acs.jmedchem.2c01317
J Exp Clin Cancer Res. 2023 Feb 07. 42(1): 42

GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT.

Tin Tin Manh Nguyen, Thi Ha Nguyen, Han Sun Kim, Thien T P Dao, Yechan Moon, Munjun Seo, Sunmi Kang, Van-Hieu Mai, Yong Jin An, Cho-Rok Jung, Jin-Mo Kim, Sunghyouk Park.

   BACKGROUND: Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained.
METHODS: Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8's involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement.
RESULTS: GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content.
CONCLUSIONS: Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes.

Keywords:  AMPK; Clear cell renal cell carcinoma (ccRCC); De novo lipogenesis (DNL); GPX8; NNMT

DOI:  https://doi.org/10.1186/s13046-023-02607-2
Proc Natl Acad Sci U S A. 2023 Feb 14. 120(7): e2217673120

Gaucher disease protects against tuberculosis.

Jingwen Fan, Victoria L Hale, Lindsey T Lelieveld, Laura J Whitworth, Elisabeth M Busch-Nentwich, Mark Troll, Paul H Edelstein, Timothy M Cox, Francisco J Roca, Johannes M F G Aerts, Lalita Ramakrishnan.

  Biallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.

Keywords:  Gaucher disease; lysosomal glucosylsphingosine; macrophages; tuberculosis resistance; zebrafish

DOI:  https://doi.org/10.1073/pnas.2217673120
Cancer Res. 2023 Feb 08. pii: CAN-22-2586. [Epub ahead of print]

Mutated HRAS activates YAP1-AXL signaling to drive metastasis of head and neck cancer.

Sankar Jagadeeshan, Manu Prasad, Mai Badarni, Talal Ben Lulu, Vijayasteltar Belsamma Liju, Sooraj Mathukkada, Claire Saunders, Avital Beeri Shnerb, Jonathan Zorea, Ksenia M Yegodayev, Monica Wainer, Liza Vtorov, Irit Allon, Ofir Cohen, Gro Gausdal, Dinorah Friedmann-Morvinski, Sok Ching Cheong, Alan L Ho, Ari J Rosenberg, Linda Kessler, Francis Burrows, Dexin Kong, Jennifer R Grandis, J Silvio Gutkind, Moshe Elkabets.

The survival rate for head and neck cancer (HNC) patients diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts (PDXs), and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2586
Nat Commun. 2023 Feb 09. 14(1): 551

Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death.

Waqar Arif, Bhoomika Mathur, Michael F Saikali, Ullas V Chembazhi, Katelyn Toohill, You Jin Song, Qinyu Hao, Saman Karimi, Steven M Blue, Brian A Yee, Eric L Van Nostrand, Sushant Bangru, Grace Guzman, Gene W Yeo, Kannanganattu V Prasanth, Sayeepriyadarshini Anakk, Carolyn L Cummins, Auinash Kalsotra.

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.

DOI: https://doi.org/10.1038/s41467-023-35932-3
Nat Commun. 2023 Feb 10. 14(1): 749

Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer.

Haochen Zhang, Elias-Ramzey Karnoub, Shigeaki Umeda, Ronan Chaligné, Ignas Masilionis, Caitlin A McIntyre, Palash Sashittal, Akimasa Hayashi, Amanda Zucker, Katelyn Mullen, Jungeui Hong, Alvin Makohon-Moore, Christine A Iacobuzio-Donahue.

Despite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve the admixture of normal and tumor cells, and/or of distinct tumor subclones; high-throughput single-cell DNA sequencing circumvents these and brings cancer genomic studies to higher resolution. However, its application has been limited to liquid tumors or a small batch of solid tumors, mainly because of the lack of a scalable workflow to process solid tumor samples. Here we optimize a highly automated nuclei extraction workflow that achieves fast and reliable targeted single-nucleus DNA library preparation of 38 samples from 16 pancreatic ductal adenocarcinoma patients, with an average library yield per sample of 2867 single nuclei. We demonstrate that this workflow not only performs well using low cellularity or low tumor purity samples but reveals genomic evolution patterns of pancreatic ductal adenocarcinoma as well.

DOI: https://doi.org/10.1038/s41467-023-36344-z
J Clin Invest. 2023 Feb 09. pii: e165863. [Epub ahead of print]

EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer.

Xiaochao Tan, Guan-Yu Xiao, Shike Wang, Lei Shi, Yanbin Zhao, Xin Liu, Jiang Yu, William K Russell, Chad J Creighton, Jonathan M Kurie.

  Hypersecretory malignant cells underlie therapeutic resistance, metastasis, and poor clinical outcomes. However, the molecular basis for malignant hypersecretion remains obscure. Here, we showed that epithelial-to-mesenchymal transition (EMT) initiates exocytic and endocytic vesicular trafficking programs in lung cancer. The EMT-activating transcription factor ZEB1 executed a PI4KIIIβ-to-PI4KIIα (PI4K2A)-dependency switch that drove PI4P synthesis in Golgi and endosomes. EMT enhanced the vulnerability of lung cancer cells to PI4K2A small molecule antagonists. PI4K2A formed a MYOIIA-containing protein complex that facilitated secretory vesicle biogenesis in the Golgi, thereby establishing a hypersecretory state involving osteopontin (SPP1) and other pro-metastatic ligands. In the endosomal compartment, PI4K2A accelerated recycling of SPP1 receptors to complete an SPP1-dependent autocrine loop and interacted with HSP90 to prevent lysosomal degradation of AXL receptor tyrosine kinase, a driver of cell migration. These results show that EMT coordinates exocytic and endocytic vesicular trafficking to establish a therapeutically actionable hypersecretory state that drives lung cancer progression.

Keywords:  Cancer gene therapy; Cell Biology; Lung cancer; Oncogenes; Oncology

DOI:  https://doi.org/10.1172/JCI165863
Nat Rev Urol. 2023 Feb 10.

Metabolic flexibility in ccRCC.

Louise Stone.

DOI: https://doi.org/10.1038/s41585-023-00734-1
Metabolomics. 2023 Feb 07. 19(2): 12

Ischemia promotes acyl-CoAs dephosphorylation and propionyl-CoA accumulation.

Wentao He, Jessica M Berthiaume, Stephen Previs, Takhar Kasumov, Guo-Fang Zhang.

   INTRODUCTION: Our untargeted metabolic data unveiled that Acyl-CoAs undergo dephosphorylation, however little is known about these novel metabolites and their physiology/pathology relevance.
OBJECTIVES: To understand the relationship between acyl-CoAs dephosphorylation and energy status as implied in our previous work, we seek to investigate how ischemia (energy depletion) triggers metabolic changes, specifically acyl-CoAs dephosphorylation in this work.
METHODS: Rat hearts were isolated and perfused in Langendorff mode for 15 min followed by 0, 5, 15, and 30 minutes of global ischemia. The heart tissues were harvested for metabolic analysis.
RESULTS: As expected, ATP and phosphocreatine were significantly decreased during ischemia. Most short- and medium-chain acyl-CoAs progressively increased with ischemic time from 0 to 15 min, whereas a 30-minute ischemia did not lead to further change. Unlike other acyl-CoAs, propionyl-CoA accumulated progressively in the hearts that underwent ischemia from 0 to 30 min. Progressive dephosphorylation occurred to all assayed acyl-CoAs and free CoA regardless their level changes during the ischemia.
CONCLUSION: The present work further confirms that dephosphorylation of acyl-CoAs is an energy-dependent process and how this dephosphorylation is mediated warrants further investigations. It is plausible that dephosphorylation of acyl-CoAs and limited anaplerosis are involved in ischemic injuries to heart. Further investigations are warranted to examine the mechanisms of acyl-CoA dephosphorylation and how the dephosphorylation is possibly involved in ischemic injuries.

Keywords:  Acyl-CoA; Acyl-dephospho-CoA; Cardiac energy metabolism; Myocardial ischemia; Propionyl-CoA

DOI:  https://doi.org/10.1007/s11306-023-01975-2
Nat Commun. 2023 Feb 08. 14(1): 684

Spatially non-uniform condensates emerge from dynamically arrested phase separation.

Nadia A Erkamp, Tomas Sneideris, Hannes Ausserwöger, Daoyuan Qian, Seema Qamar, Jonathon Nixon-Abell, Peter St George-Hyslop, Jeremy D Schmit, David A Weitz, Tuomas P J Knowles.

The formation of biomolecular condensates through phase separation from proteins and nucleic acids is emerging as a spatial organisational principle used broadly by living cells. Many such biomolecular condensates are not, however, homogeneous fluids, but possess an internal structure consisting of distinct sub-compartments with different compositions. Notably, condensates can contain compartments that are depleted in the biopolymers that make up the condensate. Here, we show that such double-emulsion condensates emerge via dynamically arrested phase transitions. The combination of a change in composition coupled with a slow response to this change can lead to the nucleation of biopolymer-poor droplets within the polymer-rich condensate phase. Our findings demonstrate that condensates with a complex internal architecture can arise from kinetic, rather than purely thermodynamic driving forces, and provide more generally an avenue to understand and control the internal structure of condensates in vitro and in vivo.

DOI: https://doi.org/10.1038/s41467-023-36059-1
Cell. 2023 Feb 02. pii: S0092-8674(22)01630-0. [Epub ahead of print]

Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice.

Yuta Takahashi, Mariana Morales Valencia, Yang Yu, Yasuo Ouchi, Kazuki Takahashi, Maxim Nikolaievich Shokhirev, Kathryn Lande, April E Williams, Chiara Fresia, Masakazu Kurita, Tomoaki Hishida, Kensaku Shojima, Fumiyuki Hatanaka, Estrella Nuñez-Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte.

  Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.

Keywords:  CpG island; DNA methylation; DNA methylation-edited mice; DNA methylation-edited mouse ES cells; biological evolution; epigenome; epimutation; obesity; transgenerational epigenetic inheritance; transmission of metabolic phenotypes

DOI:  https://doi.org/10.1016/j.cell.2022.12.047