{"doi":"10.1101/2020.09.05.284430","title":"Limitation of phosphate assimilation maintains cytoplasmic magnesium homeostasis","abstract":"Abstract Phosphorus (P) is an essential component of several core biological molecules. In bacteria, P is mainly acquired as inorganic orthophosphate (Pi). Once in the cytoplasm, Pi is incorporated into adenosine triphosphate (ATP), which exists primarily as a Mg 2+ salt. Notably, whereas P is essential, excess of cytosolic Pi hinders growth. Here we demonstrate that cytotoxic effects of excessive Pi uptake result from its assimilation into ATP and subsequent disruption of Mg 2+ dependent processes. We show that Salmonella enterica cells experiencing cytoplasmic Mg 2+ starvation restrict Pi uptake, thereby limiting the availability of an ATP precursor. This response prevents excessive ATP synthesis, overproduction of ribosomal RNA, chelation of free cytoplasmic Mg 2+ and the destabilization of Mg 2+ -dependent core processes that ultimately hinder bacterial growth and leads to loss of cellular viability. We demonstrate that, even when cytoplasmic Mg 2+ is not limiting, excessive Pi uptake leads to increased ATP synthesis, depletion of free cytoplasmic Mg 2+ , inhibition of translation and growth. Our results establish that bacteria must restrict Pi uptake to prevent the depletion of cytoplasmic Mg 2+ . Furthermore, they provide a framework to understand the molecular basis of Pi cytotoxicity and reveal a regulatory logic employed by bacterial cells to control P assimilation. Importance Phosphorus (P) is essential for life. As the fifth most abundant element in living cells, P is required for the synthesis of an array of biological molecules including (d)NTPs, nucleic acids and membranes. Organisms typically acquire environmental P as inorganic phosphate. While essential for growth and viability, excessive intracellular Pi is toxic for both bacteria and eukaryotes. Using the bacterium Salmonella enterica as a model, we demonstrate that Pi cytotoxicity is manifested following its assimilation into ATP, which acts as a chelating agent for intracellular cations, most notably, Mg 2+ . These results identify physiological processes disrupted by excessive Pi and elucidate a regulatory logic employed by bacteria to prevent uncontrollable P assimilation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124012,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567745,"name":"Christopher G. Kendra","orcid":"0000-0001-5614-9515","position":1,"is_corresponding":false},{"id":312377,"name":"Eduardo A. Groisman","orcid":"0000-0001-6860-7691","position":2,"is_corresponding":false},{"id":312376,"name":"Mauricio H. Pontes","orcid":"0000-0002-2618-2039","position":3,"is_corresponding":false},{"id":567744,"name":"Roberto E. Bruna","orcid":"0000-0002-8900-9575","position":0,"is_corresponding":true}],"reference_count":101,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}