Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing
IntroductionA considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cells in vitro and in vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not...
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Frontiers Media S.A.
2025-06-01
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| author | Emma Naomi James Muy-Teck Teh Yufeng Li Christine Wagner-Bock Zahra Falah Al-Khateeb Lee Peng Karen-Ng Terry Roberts Linnea Synchyshyn Amy Lewis Ana O’Loghlen Andrew Silver Adina Teodora Michael-Titus Mark Bennett Jacob Guy Bundy Maria Elzbieta Mycielska Eric Kenneth Parkinson |
| author_facet | Emma Naomi James Muy-Teck Teh Yufeng Li Christine Wagner-Bock Zahra Falah Al-Khateeb Lee Peng Karen-Ng Terry Roberts Linnea Synchyshyn Amy Lewis Ana O’Loghlen Andrew Silver Adina Teodora Michael-Titus Mark Bennett Jacob Guy Bundy Maria Elzbieta Mycielska Eric Kenneth Parkinson |
| author_sort | Emma Naomi James |
| collection | DOAJ |
| description | IntroductionA considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cells in vitro and in vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear.MethodsEC following various drug and cytokine treatments was measured in human fibroblast and keratinocyte conditioned medium by gas chromatography/mass spectroscopy and liquid chromatography/mass spectroscopy. Membrane transporters in similar human fibroblasts cultures were measured by western blotting and more extensively by reverse transcription and quantitative polymerase chain reaction (qPCR) in human fibroblasts, keratinocytes, myoblasts, adipocytes and astrocytes. Mouse tissues were tested for senescence markers and by qPCR, immunofluorescence and immunoFISH telomere associated foci (TAF) staining. Cytokine levels in conditioned medium were measured by the enzyme-linked immunosorbent assay and in mouse brain tissue and plasma samples using the V-PLEX proinflammatory panel 1 mouse kit.Results and DiscussionWe show here that EC is partially mediated by a newly described plasma membrane citrate transporter ANKH/SLC62A1 (progressive human ankylosis -ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/or ANKH are regulated by telomere dysfunction, the p38 mitogen-activated kinase axis, transforming growth factor beta and p53, but in contrast not by steroids, sodium butyrate, or Ataxia Telangiectasia Mutated (ATM). ANKH was upregulated in other senescent cell types relevant to ageing but not keratinocytes. In contrast, EC and ANKH were inhibited by interleukin 1α (IL-1α) in dividing and senescent fibroblasts, accompanied by an increase in IL-6 secretion. Loss- and gain of function mutations of ANKH/Ank are associated with disease and interestingly, Ank is also downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and several cytokines, suggesting that inflammatory cytokines could inhibit EC production in vivo. These data identify ANKH/Ank as a novel regulator of senescence-derived EC in both humans and mice. |
| format | Article |
| id | doaj-art-5be8f9d44f454cf7a82fabb04bbb3e16 |
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| issn | 2673-6217 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-5be8f9d44f454cf7a82fabb04bbb3e162025-08-20T02:31:48ZengFrontiers Media S.A.Frontiers in Aging2673-62172025-06-01610.3389/fragi.2025.15832881583288Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageingEmma Naomi James0Muy-Teck Teh1Yufeng Li2Christine Wagner-Bock3Zahra Falah Al-Khateeb4Lee Peng Karen-Ng5Terry Roberts6Linnea Synchyshyn7Amy Lewis8Ana O’Loghlen9Andrew Silver10Adina Teodora Michael-Titus11Mark Bennett12Jacob Guy Bundy13Maria Elzbieta Mycielska14Eric Kenneth Parkinson15Centre for Oral Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomCentre for Oral Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomDepartment of Metabolism, Digestion and Reproduction, Imperial College London, London, United KingdomUniversitätsklinikum Regensburg, Department of Dermatology, Regensburg, GermanyCentre for Neuroscience, Surgery and Trauma, Blizard Institute, London, United KingdomCentre for Oral Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomDivision of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance, College of Health and Life Sciences, Brunel University London, Uxbridge, United KingdomCentre for Oral Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomCentre for Genomics and Child Health, Colorectal Cancer Genetics Group, London, United KingdomCentre for Genomics and Child Health, London, United KingdomCentre for Genomics and Child Health, Colorectal Cancer Genetics Group, London, United KingdomCentre for Neuroscience, Surgery and Trauma, Blizard Institute, London, United KingdomDepartment of Life Sciences, Imperial College London, London, United KingdomDepartment of Metabolism, Digestion and Reproduction, Imperial College London, London, United KingdomDepartment of Structural Biology, Institute of Biophysics and Physical Biochemistry, University of Regensburg, Regensburg, GermanyCentre for Oral Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomIntroductionA considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cells in vitro and in vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear.MethodsEC following various drug and cytokine treatments was measured in human fibroblast and keratinocyte conditioned medium by gas chromatography/mass spectroscopy and liquid chromatography/mass spectroscopy. Membrane transporters in similar human fibroblasts cultures were measured by western blotting and more extensively by reverse transcription and quantitative polymerase chain reaction (qPCR) in human fibroblasts, keratinocytes, myoblasts, adipocytes and astrocytes. Mouse tissues were tested for senescence markers and by qPCR, immunofluorescence and immunoFISH telomere associated foci (TAF) staining. Cytokine levels in conditioned medium were measured by the enzyme-linked immunosorbent assay and in mouse brain tissue and plasma samples using the V-PLEX proinflammatory panel 1 mouse kit.Results and DiscussionWe show here that EC is partially mediated by a newly described plasma membrane citrate transporter ANKH/SLC62A1 (progressive human ankylosis -ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/or ANKH are regulated by telomere dysfunction, the p38 mitogen-activated kinase axis, transforming growth factor beta and p53, but in contrast not by steroids, sodium butyrate, or Ataxia Telangiectasia Mutated (ATM). ANKH was upregulated in other senescent cell types relevant to ageing but not keratinocytes. In contrast, EC and ANKH were inhibited by interleukin 1α (IL-1α) in dividing and senescent fibroblasts, accompanied by an increase in IL-6 secretion. Loss- and gain of function mutations of ANKH/Ank are associated with disease and interestingly, Ank is also downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and several cytokines, suggesting that inflammatory cytokines could inhibit EC production in vivo. These data identify ANKH/Ank as a novel regulator of senescence-derived EC in both humans and mice.https://www.frontiersin.org/articles/10.3389/fragi.2025.1583288/fullANKH/SLC62A1citratesenescenceageinginflammationastrocyte |
| spellingShingle | Emma Naomi James Muy-Teck Teh Yufeng Li Christine Wagner-Bock Zahra Falah Al-Khateeb Lee Peng Karen-Ng Terry Roberts Linnea Synchyshyn Amy Lewis Ana O’Loghlen Andrew Silver Adina Teodora Michael-Titus Mark Bennett Jacob Guy Bundy Maria Elzbieta Mycielska Eric Kenneth Parkinson Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing Frontiers in Aging ANKH/SLC62A1 citrate senescence ageing inflammation astrocyte |
| title | Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing |
| title_full | Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing |
| title_fullStr | Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing |
| title_full_unstemmed | Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing |
| title_short | Membrane transporter progressive ankylosis protein homologue (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation, and ageing |
| title_sort | membrane transporter progressive ankylosis protein homologue ankh ank partially mediates senescence derived extracellular citrate and is regulated by dna damage inflammation and ageing |
| topic | ANKH/SLC62A1 citrate senescence ageing inflammation astrocyte |
| url | https://www.frontiersin.org/articles/10.3389/fragi.2025.1583288/full |
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