Evolutionary perspective on mammalian inorganic polyphosphate (polyP) biology

Inorganic polyphosphate (polyP), the polymeric form of phosphate, is attracting ever-growing attention due to the many functions it appears to perform within mammalian cells. This essay does not aim to systematically review the copious mammalian polyP literature. Instead, we examined polyP synthesis and functions in various microorganisms and used an evolutionary perspective to theorise key issues of this field and propose solutions. By highlighting the presence of VTC4 in distinct species of very divergent eucaryote clades (Opisthokonta, Viridiplantae, Discoba, and the SAR), we propose that whilst polyP synthesising machinery was present in the ancestral eukaryote, most lineages subsequently lost it during evolution. The analysis of the bacteria-acquired amoeba PPK1 and its unique polyP physiology suggests that eukaryote cells must have developed mechanisms to limit cytosolic polyP accumulation. We reviewed the literature on polyP in the mitochondria from the perspective of its endosymbiotic origin from bacteria, highlighting how mitochondria could possess a polyP physiology reminiscent of their ‘bacterial’ beginning that is not yet investigated. Finally, we emphasised the similarities that the anionic polyP shares with the better-understood negatively charged polymers DNA and RNA, postulating that the nucleus offers an ideal environment where polyP physiology might thrive.

[1]  Carsten A. Wagner The basics of phosphate metabolism , 2023, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  N. Perrimon,et al.  A phosphate-sensing organelle regulates phosphate and tissue homeostasis , 2023, Nature.

[3]  A. Mayer,et al.  Cryo‐EM structure of the polyphosphate polymerase VTC reveals coupling of polymer synthesis to membrane transit , 2023, The EMBO journal.

[4]  R. Gomer,et al.  Starvation Induces Extracellular Accumulation of Polyphosphate in Dictyostelium discoideum to Inhibit Macropinocytosis, Phagocytosis, and Exocytosis , 2023, bioRxiv.

[5]  J. Zhang,et al.  The cytoplasmic synthesis and coupled membrane translocation of eukaryotic polyphosphate by signal-activated VTC complex , 2023, Nature Communications.

[6]  M. Downey,et al.  The emerging landscape of eukaryotic polyphosphatases , 2023, FEBS letters.

[7]  D. Fiedler,et al.  Nucleolar Architecture Is Modulated by a Small Molecule, the Inositol Pyrophosphate 5-InsP7 , 2023, Biomolecules.

[8]  Yufeng Xi,et al.  Vesicle trafficking and vesicle fusion: mechanisms, biological functions, and their implications for potential disease therapy , 2022, Molecular Biomedicine.

[9]  R. Smolenski,et al.  Inorganic Polyphosphate—Regulator of Cellular Metabolism in Homeostasis and Disease , 2022, Biomedicines.

[10]  D. Raftery,et al.  Enzymatic Depletion of Mitochondrial Inorganic Polyphosphate (polyP) Increases the Generation of Reactive Oxygen Species (ROS) and the Activity of the Pentose Phosphate Pathway (PPP) in Mammalian Cells , 2022, Antioxidants.

[11]  O. McCarty,et al.  Effects of ex vivo blood anticoagulation and preanalytical processing time on the proteome content of platelets , 2022, Journal of thrombosis and haemostasis : JTH.

[12]  Gennifer E. Merrihew,et al.  Mitochondrial Inorganic Polyphosphate (polyP) Is a Potent Regulator of Mammalian Bioenergetics in SH-SY5Y Cells: A Proteomics and Metabolomics Study , 2022, Frontiers in Cell and Developmental Biology.

[13]  M. Lavallée-Adam,et al.  Ddp1 Cooperates with Ppx1 to Counter a Stress Response Initiated by Nonvacuolar Polyphosphate , 2022, bioRxiv.

[14]  A. Saiardi,et al.  Polyphosphate degradation by Nudt3-Zn2+ mediates oxidative stress response. , 2021, Cell reports.

[15]  A. Saiardi,et al.  The inositol pyrophosphate metabolism of Dictyostelium discoideum does not regulate inorganic polyphosphate (polyP) synthesis , 2021, Advances in biological regulation.

[16]  Bao Zhang,et al.  Polyphosphate Kinase 1 Is a Pathogenesis Determinant in Enterohemorrhagic Escherichia coli O157:H7 , 2021, Frontiers in Microbiology.

[17]  D. Raftery,et al.  Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis. , 2021, The Biochemical journal.

[18]  A. Mayer,et al.  The chemistry of branched condensed phosphates , 2021, Nature communications.

[19]  Anisha Shakya,et al.  Phase Separation of DNA: From Past to Present. , 2021, Biophysical journal.

[20]  M. Lavallée-Adam,et al.  A Broad Response to Intracellular Long-Chain Polyphosphate in Human Cells. , 2020, Cell reports.

[21]  Joshua A. Riback,et al.  The nucleolus as a multiphase liquid condensate , 2020, Nature Reviews Molecular Cell Biology.

[22]  M. Lavallée-Adam,et al.  A broad response to intracellular long-chain polyphosphate in human cells , 2020, bioRxiv.

[23]  A. Saiardi,et al.  Inorganic polyphosphate in mammals: where's Wally? , 2020, Biochemical Society transactions.

[24]  U. Jakob,et al.  Accumulation of Nucleolar Inorganic Polyphosphate Is a Cellular Response to Cisplatin-Induced Apoptosis , 2019, Front. Oncol..

[25]  Joshua C. Chang,et al.  Inorganic polyphosphate is required for sustained free mitochondrial calcium elevation, following calcium uptake. , 2019, Cell calcium.

[26]  Chen-Yu Shi,et al.  An Inorganic Biopolymer Polyphosphate Controls Positively Charged Protein Phase Transitions. , 2019, Angewandte Chemie.

[27]  W. Müller,et al.  Inorganic Polyphosphates As Storage for and Generator of Metabolic Energy in the Extracellular Matrix , 2019, Chemical reviews.

[28]  Yan Wang,et al.  Progress and Applications of Polyphosphate in Bone and Cartilage Regeneration , 2019, BioMed research international.

[29]  T. Renné,et al.  Polyphosphate as a Target for Interference With Inflammation and Thrombosis , 2019, Front. Med..

[30]  M. Downey A Stringent Analysis of Polyphosphate Dynamics in Escherichia coli , 2019, Journal of bacteriology.

[31]  Askar Yimit,et al.  Differential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs , 2019, Nature Communications.

[32]  U. Jakob,et al.  Inorganic polyphosphate, a multifunctional polyanionic protein scaffold , 2018, The Journal of Biological Chemistry.

[33]  A. Saiardi,et al.  Screening a Protein Array with Synthetic Biotinylated Inorganic Polyphosphate To Define the Human PolyP-ome. , 2018, ACS chemical biology.

[34]  Liang Wang,et al.  Distribution Patterns of Polyphosphate Metabolism Pathway and Its Relationships With Bacterial Durability and Virulence , 2018, Front. Microbiol..

[35]  Norman E. Davey,et al.  A Screen for Candidate Targets of Lysine Polyphosphorylation Uncovers a Conserved Network Implicated in Ribosome Biogenesis. , 2018, Cell reports.

[36]  T. Knöpfel,et al.  The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction , 2017, Scientific Reports.

[37]  E. Garí,et al.  Polyphosphate is a key factor for cell survival after DNA damage in eukaryotic cells. , 2017, DNA repair.

[38]  A. Saiardi,et al.  Eukaryotic Phosphate Homeostasis: The Inositol Pyrophosphate Perspective. , 2017, Trends in biochemical sciences.

[39]  F. Torti,et al.  Mitochondria and Iron: current questions , 2017, Expert review of hematology.

[40]  M. Chapman,et al.  Polyphosphate: A Conserved Modifier of Amyloidogenic Processes. , 2016, Molecular cell.

[41]  R. Gomer,et al.  Extracellular Polyphosphate Inhibits Proliferation in an Autocrine Negative Feedback Loop in Dictyostelium discoideum* , 2016, The Journal of Biological Chemistry.

[42]  Diana M. Mitrea,et al.  Coexisting Liquid Phases Underlie Nucleolar Subcompartments , 2016, Cell.

[43]  J. Clotet,et al.  Polyphosphate: popping up from oblivion , 2016, Current Genetics.

[44]  A. Mayer,et al.  Enzymes of yeast polyphosphate metabolism: structure, enzymology and biological roles. , 2016, Biochemical Society transactions.

[45]  A. Saiardi,et al.  Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum , 2016, Proceedings of the National Academy of Sciences.

[46]  W. Kühlbrandt,et al.  Structure and function of mitochondrial membrane protein complexes , 2015, BMC Biology.

[47]  J. Archibald,et al.  Endosymbiosis and Eukaryotic Cell Evolution , 2015, Current Biology.

[48]  G. Hajnóczky,et al.  The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease. , 2015, Biochemical and biophysical research communications.

[49]  R. Rossignol,et al.  Redox Homeostasis and Mitochondrial Dynamics. , 2015, Cell metabolism.

[50]  J. Morrissey,et al.  Polyphosphate as modulator of hemostasis, thrombosis, and inflammation , 2015, Journal of thrombosis and haemostasis : JTH.

[51]  A. Saiardi,et al.  Protein polyphosphorylation of lysine residues by inorganic polyphosphate. , 2015, Molecular cell.

[52]  U. Jakob,et al.  Oxidative stress protection by polyphosphate--new roles for an old player. , 2015, Current opinion in microbiology.

[53]  S. Gribaldo,et al.  Eukaryotic origins: How and when was the mitochondrion acquired? , 2014, Cold Spring Harbor perspectives in biology.

[54]  A. Mayer,et al.  Coupled synthesis and translocation restrains polyphosphate to acidocalcisome-like vacuoles and prevents its toxicity , 2014, Journal of Cell Science.

[55]  R. Manorama,et al.  Inositol pyrophosphates regulate RNA polymerase I-mediated rRNA transcription in Saccharomyces cerevisiae , 2014, The Biochemical journal.

[56]  B. Stillman Deoxynucleoside triphosphate (dNTP) synthesis and destruction regulate the replication of both cell and virus genomes , 2013, Proceedings of the National Academy of Sciences.

[57]  A. Saiardi,et al.  Inositol pyrophosphates: between signalling and metabolism. , 2013, The Biochemical journal.

[58]  Maria D Jimenez-Nuñez,et al.  Myeloma cells contain high levels of inorganic polyphosphate which is associated with nucleolar transcription , 2012, Haematologica.

[59]  Hui Xiao,et al.  Lysine post-translational modifications and the cytoskeleton. , 2012, Essays in biochemistry.

[60]  A. Saiardi,et al.  Identification of an Evolutionarily Conserved Family of Inorganic Polyphosphate Endopolyphosphatases* , 2011, The Journal of Biological Chemistry.

[61]  Michelle S. Scott,et al.  Characterization and prediction of protein nucleolar localization sequences , 2010, Nucleic acids research.

[62]  A. Saiardi,et al.  Are inositol pyrophosphates signalling molecules? , 2009, Journal of cellular physiology.

[63]  E. Zakharian,et al.  Inorganic Polyphosphate Modulates TRPM8 Channels , 2009, PloS one.

[64]  K. Mizuta,et al.  Genetic Interaction between Ribosome Biogenesis and Inositol Polyphosphate Metabolism in Saccharomyces cerevisiae , 2009, Bioscience, biotechnology, and biochemistry.

[65]  Maria D Jimenez-Nuñez,et al.  Organellar proteomics of human platelet dense granules reveals that 14-3-3zeta is a granule protein related to atherosclerosis. , 2007, Journal of proteome research.

[66]  Troels Z. Kristiansen,et al.  Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event , 2007, Proceedings of the National Academy of Sciences.

[67]  Anil Kumar Singh,et al.  Polyphosphate kinase is involved in stress‐induced mprAB‐sigE‐rel signalling in mycobacteria , 2007, Molecular microbiology.

[68]  James H Morrissey,et al.  Polyphosphate modulates blood coagulation and fibrinolysis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[69]  U. Walter,et al.  The Human Platelet Membrane Proteome Reveals Several New Potential Membrane Proteins*S , 2005, Molecular & Cellular Proteomics.

[70]  S. Snyder,et al.  Phosphorylation of Proteins by Inositol Pyrophosphates , 2004, Science.

[71]  E. Oldfield,et al.  Human Platelet Dense Granules Contain Polyphosphate and Are Similar to Acidocalcisomes of Bacteria and Unicellular Eukaryotes* , 2004, Journal of Biological Chemistry.

[72]  R. Dwek,et al.  Extensive analysis of the human platelet proteome by two‐dimensional gel electrophoresis and mass spectrometry , 2004, Proteomics.

[73]  A. Kornberg Inorganic polyphosphate: a molecule of many functions. , 2003, Annual review of biochemistry.

[74]  A. Kornberg,et al.  Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[75]  A. Kornberg,et al.  A polyphosphate kinase (PPK2) widely conserved in bacteria , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[76]  T. Kulakovskaya,et al.  The development of A. N. Belozersky's ideas in polyphosphate biochemistry. , 2000, Biochemistry. Biokhimiia.

[77]  Xiaonian Yang,et al.  A novel context for the ‘MutT’ module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase , 1998, The EMBO journal.

[78]  A. Kornberg,et al.  Inorganic Polyphosphate in Mammalian Cells and Tissues (*) , 1995, The Journal of Biological Chemistry.

[79]  A. Kornberg Inorganic polyphosphate: toward making a forgotten polymer unforgettable , 1995, Journal of bacteriology.

[80]  P. Pedersen,et al.  Phosphate transport in mitochondria: Past accomplishments, present problems, and future challenges , 1993, Journal of Bioenergetics and Biomembranes.

[81]  A. Kornberg,et al.  The polyphosphate kinase gene of Escherichia coli. Isolation and sequence of the ppk gene and membrane location of the protein. , 1992, The Journal of biological chemistry.

[82]  J. Griffin,et al.  Studies of phosphorus metabolism by isolated nuclei. VII. Identification of polyphosphate as a product. , 1965, The Journal of biological chemistry.

[83]  W. Lynn,et al.  Synthesis of polyphosphate by rat liver mitochondria. , 1963, Biochemical and biophysical research communications.

[84]  E. Pavlov,et al.  Inorganic Polyphosphate in Mitochondrial Energy Metabolism and Pathology. , 2022, Progress in molecular and subcellular biology.

[85]  Pedro Urquiza,et al.  Inorganic Polyphosphate, Mitochondria, and Neurodegeneration. , 2022, Progress in molecular and subcellular biology.

[86]  Adolfo Saiardi,et al.  Why always lysine? The ongoing tale of one of the most modified amino acids. , 2016, Advances in biological regulation.