bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022‒05‒22
eighteen papers selected by
Catalina Vasilescu
University of Helsinki
  1. Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
  2. A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data.
  3. TALEDs complete the toolkit for editing human mitochondrial DNA.
  4. SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
  5. Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
  6. Cutting the Gordian Knot of a Mitochondrial Disease.
  7. Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases.
  8. Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.
  9. Mitochondrial-derived vesicles: Recent insights.
  10. Neuron-astrocyte transmitophagy is altered in Alzheimer's disease.
  11. The Natural History of Leber's Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers.
  12. Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.
  13. Deep Visual Proteomics defines single-cell identity and heterogeneity.
  14. Machine learning approaches to explore digenic inheritance.
  15. Recommendations for whole genome sequencing in diagnostics for rare diseases.
  16. Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis.
  17. Ultrarapid Nanopore Genome Sequencing Speeds up Diagnosis in a Critical Care Setting.
  18. Actin polymerization induces mitochondrial distribution during collective cell migration.
  1. Nat Commun. 2022 May 19. 13(1): 2758
    Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
    Injae Chung, John J Wright, Hannah R Bridges, Bozhidar S Ivanov, Olivier Biner, Caroline S Pereira, Guilherme M Arantes, Judy Hirst.
      Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q10 reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the 'active' (ready-to-go) resting state together with a matching substrate-free structure, and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the 'deactive' resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.
    DOI:  https://doi.org/10.1038/s41467-022-30506-1
  2. NAR Genom Bioinform. 2022 Jun;4(2): lqac034
    A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data.
    TOPMed mtDNA Working Group
      Mitochondrial diseases are a heterogeneous group of disorders that can be caused by mutations in the nuclear or mitochondrial genome. Mitochondrial DNA (mtDNA) variants may exist in a state of heteroplasmy, where a percentage of DNA molecules harbor a variant, or homoplasmy, where all DNA molecules have the same variant. The relative quantity of mtDNA in a cell, or copy number (mtDNA-CN), is associated with mitochondrial function, human disease, and mortality. To facilitate accurate identification of heteroplasmy and quantify mtDNA-CN, we built a bioinformatics pipeline that takes whole genome sequencing data and outputs mitochondrial variants, and mtDNA-CN. We incorporate variant annotations to facilitate determination of variant significance. Our pipeline yields uniform coverage by remapping to a circularized chrM and by recovering reads falsely mapped to nuclear-encoded mitochondrial sequences. Notably, we construct a consensus chrM sequence for each sample and recall heteroplasmy against the sample's unique mitochondrial genome. We observe an approximately 3-fold increased association with age for heteroplasmic variants in non-homopolymer regions and, are better able to capture genetic variation in the D-loop of chrM compared to existing software. Our bioinformatics pipeline more accurately captures features of mitochondrial genetics than existing pipelines that are important in understanding how mitochondrial dysfunction contributes to disease.
    DOI:  https://doi.org/10.1093/nargab/lqac034
  3. Nat Struct Mol Biol. 2022 May;29(5): 415
    TALEDs complete the toolkit for editing human mitochondrial DNA.
    Carolina N Perdigoto.
      
    DOI:  https://doi.org/10.1038/s41594-022-00781-z
  4. Autophagy. 2022 May 19. 1-2
    SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during mitochondrial replacement therapy.
    Xiao-Yan Fan, Shen Yin, Shi-Ming Luo.
      Mitophagy is a process that selectively degrades mitochondria in cells, and it involves a series of signaling events. Our recent paper shows that the ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (Binding) at the mitochondrial outer membrane, can directly cause mitophagy. To distinguish this mitophagy from others, we called it forced mitophagy. Further results show that the forced mitophagy can degrade half of the mitochondria and their DNA in HeLa cells and mouse embryos. Meanwhile, there are no apparent effects on mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitosis and embryo development. Thus, the forced mitophagy was examined to selectively degrade mitochondrial carryover in the nuclear donor embryos' mitochondria by pre-labeling with Binding before mitochondrial replacement therapy (MRT). The results show that the forced mitophagy can reduce mitochondrial carryover from an average of 4% to 0.09% compared to the controls in mouse embryos and tissues. In addition, the offspring from MRT mice show negligible effects on growth, reproduction, exercise and behavior. Furthermore, results from human tri-pronuclear embryos show that the forced mitophagy results in undetectable mitochondrial carryover in 77% of embryos following MRT. Therefore, forced mitophagy is efficient and safe for degrading mitochondrial carryover in MRT.
    Keywords:  Forced mitophagy; NIX; SQSTM1; mitochondrial carryover; mitochondrial replacement therapy
    DOI:  https://doi.org/10.1080/15548627.2022.2077552
  5. Nat Commun. 2022 May 19. 13(1): 2769
    Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
    Enrique Balderas, David R Eberhardt, Sandra Lee, John M Pleinis, Salah Sommakia, Anthony M Balynas, Xue Yin, Mitchell C Parker, Colin T Maguire, Scott Cho, Marta W Szulik, Anna Bakhtina, Ryan D Bia, Marisa W Friederich, Timothy M Locke, Johan L K Van Hove, Stavros G Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R Rodan, Dipayan Chaudhuri.
      Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.
    DOI:  https://doi.org/10.1038/s41467-022-30236-4
  6. Med (N Y). 2021 Jan 15. pii: S2666-6340(20)30081-7. [Epub ahead of print]2(1): 11-13
    Cutting the Gordian Knot of a Mitochondrial Disease.
    Eric A Shoubridge.
      The advent of whole-exome sequencing ushered in a new era of in the genetic diagnosis of rare diseases, but characterizing large alterations in genome architecture has remained challenging. In this issue of Med, Frazier et al. harnessed the power of genomics and proteomics to identify a recurrent duplication as the molecular basis of a fatal perinatal mitochondrial cardiomyopathy.1.
    DOI:  https://doi.org/10.1016/j.medj.2020.12.015
  7. Cell Biosci. 2022 May 19. 12(1): 66
    Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases.
    Zonghan Liu, Yi Sun, Zhengtang Qi, Lu Cao, Shuzhe Ding.
      Mitochondria play a pivotal role in energy generation and cellular physiological processes. These organelles are highly dynamic, constantly changing their morphology, cellular location, and distribution in response to cellular stress. In recent years, the phenomenon of mitochondrial transfer has attracted significant attention and interest from biologists and medical investigators. Intercellular mitochondrial transfer occurs in different ways, including tunnelling nanotubes (TNTs), extracellular vesicles (EVs), and gap junction channels (GJCs). According to research on intercellular mitochondrial transfer in physiological and pathological environments, mitochondrial transfer hold great potential for maintaining body homeostasis and regulating pathological processes. Multiple research groups have developed artificial mitochondrial transfer/transplantation (AMT/T) methods that transfer healthy mitochondria into damaged cells and recover cellular function. This paper reviews intercellular spontaneous mitochondrial transfer modes, mechanisms, and the latest methods of AMT/T. Furthermore, potential application value and mechanism of AMT/T in disease treatment are also discussed.
    Keywords:  Ageing; Cancer therapy; Energy metabolism; Mitochondrial transfer; Mitochondrial transplantation; Stem cell; Tissue injury; mtDNA mutations and deletions
    DOI:  https://doi.org/10.1186/s13578-022-00805-7
  8. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac045
    Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.
    Shaobo Li, Xiaowu Gai, Swe Swe Myint, Katti Arroyo, Libby Morimoto, Catherine Metayer, Adam J de Smith, Kyle M Walsh, Joseph L Wiemels.
      Background: Childhood glioblastoma multiforme (GBM) is a highly aggressive disease with low survival, and its etiology, especially concerning germline genetic risk, is poorly understood. Mitochondria play a key role in putative tumorigenic processes relating to cellular oxidative metabolism, and mitochondrial DNA variants were not previously assessed for association with pediatric brain tumor risk.Methods: We conducted an analysis of 675 mitochondrial DNA variants in 90 childhood GBM cases and 2789 controls to identify enrichment of mitochondrial variant associated with GBM risk. We also performed this analysis for other glioma subtypes including pilocytic astrocytoma. Nuclear-encoded mitochondrial gene variants were also analyzed.
    Results: We identified m1555 A>G was significantly associated with GBM risk (adjusted OR 29.30, 95% CI 5.25-163.4, P-value 9.5 X 10-4). No association was detected for other subtypes. Haplotype analysis further supported the independent risk contributed by m1555 G>A, instead of a haplogroup joint effect. Nuclear-encoded mitochondrial gene variants identified significant associations in European (rs62036057 in WWOX, adjusted OR = 2.99, 95% CI 1.88-4.75, P-value = 3.42 X 10-6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99-6.40, P-value = 1.41 X 10-6) populations in ethnicity-stratified analyses.
    Conclusion: We report for the first time a potential role played by a functional mitochondrial ribosomal RNA variant in childhood GBM risk, and a potential role for both mitochondrial and nuclear-mitochondrial DNA polymorphisms in GBM tumorigenesis. These data implicate cellular oxidative metabolic capacity as a contributor to the etiology of pediatric glioblastoma.
    Keywords:  mitochondrial genome; pediatric glioblastoma; risk factor; variant
    DOI:  https://doi.org/10.1093/noajnl/vdac045
  9. J Cell Mol Med. 2022 May 18.
    Mitochondrial-derived vesicles: Recent insights.
    Lucia-Doina Popov.
      The generation of vesicles is a constitutive attribute of mitochondria inherited from bacterial ancestors. The physiological conditions and mild oxidative stress promote oxidation and dysfunction of certain proteins and lipids within the mitochondrial membranes; these constituents are subsequently packed as small mitochondrial-derived vesicles (MDVs) (70-150 nm in diameter) and are transported intracellularly to lysosomes and peroxisomes to be degraded. In this way, MDVs remove the damaged mitochondrial components, preserve mitochondrial structural and functional integrity and restore homeostasis. An outline of the current knowledge on MDVs seems to be necessary for understanding the potential impact of this research area in cellular (patho)physiology. The present synopsis is an attempt towards the accomplishment of this demand, highlighting also the still unclear issues related to MDVs. Here, we discuss (i) MDVs budding and generation (molecules and mechanisms), (ii) the distinct cargoes packed and transported by MDVs, (iii) the MDVs trafficking pathways and (iv) the biological role of MDVs, from quality controllers to the involvement in organellar crosstalk, mitochondrial antigen presentation and peroxisome de novo biogenesis. These complex roles uncover also mitochondria integration into the cellular environment. As the therapeutic exploitation of MDVs is currently limited, future insights into MDVs cell biology are expected to direct to novel diagnostic tools and treatments.
    Keywords:  PINK1; Parkin; Quality control; extracellular vesicles; lysosomes; peroxisome
    DOI:  https://doi.org/10.1111/jcmm.17391
  10. Neurobiol Dis. 2022 May 13. pii: S0969-9961(22)00145-0. [Epub ahead of print]170 105753
    Neuron-astrocyte transmitophagy is altered in Alzheimer's disease.
    Riikka Lampinen, Irina Belaya, Liudmila Saveleva, Jeffrey R Liddell, Dzhessi Rait, Mikko T Huuskonen, Raisa Giniatullina, Annika Sorvari, Liisi Soppela, Nikita Mikhailov, Isabella Boccuni, Rashid Giniatullin, Marcela Cruz-Haces, Julia Konovalova, Marja Koskuvi, Andrii Domanskyi, Riikka H Hämäläinen, Gundars Goldsteins, Jari Koistinaho, Tarja Malm, Sweelin Chew, Kirsi Rilla, Anthony R White, Nicholas Marsh-Armstrong, Katja M Kanninen.
      Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization of neuronal mitochondria is significantly increased in astrocytes isolated from AD mouse brains. We also demonstrate that the degradation of neuronal mitochondria by astrocytes is increased in AD mice at the age of 6 months onwards. Furthermore, we demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and AD astrocytes together with significant increases in the mitophagy regulator and reactive oxygen species in aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.
    Keywords:  Alzheimer's disease; Astrocytes; Mitochondria; Mitophagy; Transmitophagy
    DOI:  https://doi.org/10.1016/j.nbd.2022.105753
  11. Neuroophthalmology. 2022 ;46(3): 159-170
    The Natural History of Leber's Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers.
    Kirk A J Stephenson, Joseph McAndrew, Paul F Kenna, Lorraine Cassidy.
      In this study we have assessed the clinical and genetic characteristics of an Irish Leber's hereditary optic neuropathy (LHON) cohort and assessed for useful biomarkers of visual prognosis. We carried out a retrospective review of clinical data of patients with genetically confirmed LHON presenting to an Irish tertiary referral ophthalmic hospital. LHON diagnosis was made on classic clinical signs with genetic confirmation. Alternate diagnoses were excluded with serological investigations and neuro-imaging. Serial logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) was stratified into 'on-chart' for logMAR 1.0 or better and 'off-chart' if worse than logMAR 1.0. Serial optical coherence tomography scans of the retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) monitored structure. Idebenone-treated and untreated patients were contrasted. Statistical analyses were performed to assess correlations of presenting characteristics with final VA. Forty-four patients from 34 pedigrees were recruited, of which 87% were male and 75% harboured the 11778 mutation. Legal blindness status was reached in 56.8% of patients by final review (mean 74 months). Preservation of initial nasal RNFL was the best predictor of on-chart final VA. Females had worse final VA than males and patients presenting at < 20 years of age had superior final VA. Idebenone therapy (50% of cohort) yielded no statistically significant benefit to final VA, although study design precludes definitive comment on efficacy. The reported cases represent the calculated majority of LHON pedigrees in Ireland. Visual outcomes were universally poor; however, VA may not be the most appropriate outcome measure and certain patient-reported outcome measures may be of more use when assessing future LHON interventions.
    Keywords:  Leber’s hereditary optic neuropathy; idebenone; inherited optic neuropathy; mtDNA; ophthalmic genetics; optic atrophy
    DOI:  https://doi.org/10.1080/01658107.2022.2032761
  12. Nat Commun. 2022 May 16. 13(1): 2698
    Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.
    Mona Hoseini Soflaee, Rushendhiran Kesavan, Umakant Sahu, Alpaslan Tasdogan, Elodie Villa, Zied Djabari, Feng Cai, Diem H Tran, Hieu S Vu, Eunus S Ali, Halie Rion, Brendan P O'Hara, Sherwin Kelekar, James Hughes Hallett, Misty Martin, Thomas P Mathews, Peng Gao, John M Asara, Brendan D Manning, Issam Ben-Sahra, Gerta Hoxhaj.
      Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.
    DOI:  https://doi.org/10.1038/s41467-022-30362-z
  13. Nat Biotechnol. 2022 May 19.
    Deep Visual Proteomics defines single-cell identity and heterogeneity.
    Andreas Mund, Fabian Coscia, András Kriston, Réka Hollandi, Ferenc Kovács, Andreas-David Brunner, Ede Migh, Lisa Schweizer, Alberto Santos, Michael Bzorek, Soraya Naimy, Lise Mette Rahbek-Gjerdrum, Beatrice Dyring-Andersen, Jutta Bulkescher, Claudia Lukas, Mark Adam Eckert, Ernst Lengyel, Christian Gnann, Emma Lundberg, Peter Horvath, Matthias Mann.
      Despite the availabilty of imaging-based and mass-spectrometry-based methods for spatial proteomics, a key challenge remains connecting images with single-cell-resolution protein abundance measurements. Here, we introduce Deep Visual Proteomics (DVP), which combines artificial-intelligence-driven image analysis of cellular phenotypes with automated single-cell or single-nucleus laser microdissection and ultra-high-sensitivity mass spectrometry. DVP links protein abundance to complex cellular or subcellular phenotypes while preserving spatial context. By individually excising nuclei from cell culture, we classified distinct cell states with proteomic profiles defined by known and uncharacterized proteins. In an archived primary melanoma tissue, DVP identified spatially resolved proteome changes as normal melanocytes transition to fully invasive melanoma, revealing pathways that change in a spatial manner as cancer progresses, such as mRNA splicing dysregulation in metastatic vertical growth that coincides with reduced interferon signaling and antigen presentation. The ability of DVP to retain precise spatial proteomic information in the tissue context has implications for the molecular profiling of clinical samples.
    DOI:  https://doi.org/10.1038/s41587-022-01302-5
  14. Trends Genet. 2022 May 14. pii: S0168-9525(22)00105-6. [Epub ahead of print]
    Machine learning approaches to explore digenic inheritance.
    Atsuko Okazaki, Jurg Ott.
      Some rare genetic disorders, such as retinitis pigmentosa or Alport syndrome, are caused by the co-inheritance of DNA variants at two different genetic loci (digenic inheritance). To capture the effects of these disease-causing variants and their possible interactive effects, various statistical methods have been developed in human genetics. Analogous developments have taken place in the field of machine learning, particularly for the field that is now called Big Data. In the past, these two areas have grown independently and have started to converge only in recent years. We discuss an overview of each of the two fields, paying special attention to machine learning methods for uncovering the combined effects of pairs of variants on human disease.
    Keywords:  digenic inheritance; epistasis; machine learning; modifier variants; statistical genetics
    DOI:  https://doi.org/10.1016/j.tig.2022.04.009
  15. Eur J Hum Genet. 2022 May 16.
    Recommendations for whole genome sequencing in diagnostics for rare diseases.
    Erika Souche, Sergi Beltran, Erwin Brosens, John W Belmont, Magdalena Fossum, Olaf Riess, Christian Gilissen, Amin Ardeshirdavani, Gunnar Houge, Marielle van Gijn, Jill Clayton-Smith, Matthis Synofzik, Nicole de Leeuw, Zandra C Deans, Yasemin Dincer, Sebastian H Eck, Saskia van der Crabben, Meena Balasubramanian, Holm Graessner, Marc Sturm, Helen Firth, Alessandra Ferlini, Rima Nabbout, Elfride De Baere, Thomas Liehr, Milan Macek, Gert Matthijs, Hans Scheffer, Peter Bauer, Helger G Yntema, Marjan M Weiss.
      In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions. The use of WGS in diagnostics warrants the re-evaluation and update of previously published guidelines. This work was jointly initiated by EuroGentest and the Horizon2020 project Solve-RD. Statements from the 2016 guidelines have been reviewed in the context of WGS and updated where necessary. The aim of these recommendations is primarily to list the points to consider for clinical (laboratory) geneticists, bioinformaticians, and (non-)geneticists, to provide technical advice, aid clinical decision-making and the reporting of the results.
    DOI:  https://doi.org/10.1038/s41431-022-01113-x
  16. Dev Cell. 2022 May 11. pii: S1534-5807(22)00286-6. [Epub ahead of print]
    Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis.
    Roxana E Oberkersch, Giovanna Pontarin, Matteo Astone, Marianna Spizzotin, Liaisan Arslanbaeva, Giovanni Tosi, Emiliano Panieri, Sara Ricciardi, Maria Francesca Allega, Alessia Brossa, Paolo Grumati, Benedetta Bussolati, Stefano Biffo, Saverio Tardito, Massimo M Santoro.
      Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.
    Keywords:  angiogenesis; aspartate metabolism; endothelial metabolism; mTOR signalling; tumor angiogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.018
  17. Am J Med Genet A. 2022 Jun;188(6): 1656-1657
    Ultrarapid Nanopore Genome Sequencing Speeds up Diagnosis in a Critical Care Setting.
      
    DOI:  https://doi.org/10.1002/ajmg.a.62297
  18. J Genet Genomics. 2022 May 13. pii: S1673-8527(22)00134-5. [Epub ahead of print]
    Actin polymerization induces mitochondrial distribution during collective cell migration.
    Chen Qu, Yating Kan, Hui, Zuo, Mengqi Wu, Zhixiang Dong, Xinyi Wang, Qing Zhang, Heng Wang, Dou Wang, Jiong Chen.
      
    DOI:  https://doi.org/10.1016/j.jgg.2022.04.014
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