{
  "abstract": "Reproductive longevity decline characterizes both natural aging and premature ovarian insufficiency (POI). While our previous work established C. elegans LMD-3 as a critical regulator of reproductive capacity, the in vivo consequences of specific clinical mutations remain unclear. Here, we modeled the POI-associated human NCOA7 W804C mutation by engineering the orthologous W690C substitution into the C. elegans lmd-3 locus. We demonstrate that this single-nucleotide substitution severely compromises LMD-3 protein stability and reduces transcript levels. This mutational destabilization is associated with profound systemic autophagic-lysosomal dysfunction, which impairs macromolecular degradation and leads to widespread proteotoxic accumulation of misfolded proteins. Coincident with these organismal defects, mutant animals exhibit an early-onset collapse in reproductive capacity driven by elevated germline apoptosis. Crucially, this pathology is consistent with reduced vitamin B12 availability; mecobalamin supplementation can mitigate the lysosomal block, restoring autophagic flux, proteostasis, and fecundity. These findings elucidate how a clinical mutation drives systemic lysosomal failure and reproductive decline, suggesting vitamin B12 supplementation as a promising metabolic intervention worth further translational exploration.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Medical Sciences, The Second Qilu Hospital of Shandong University, Jinan, Shandong, China",
    "Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China",
    "State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, Yunnan, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yile Zhai",
      "orcid": "0009-0009-9850-8585"
    },
    {
      "affs": [
        1
      ],
      "name": "Tiantian Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Meixi Gong",
      "orcid": "0009-0007-9036-1748"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuhan Liang"
    },
    {
      "affs": [
        1
      ],
      "name": "Wenfei Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Xin Wang",
      "orcid": "0000-0003-1576-7127"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhe Zhang",
      "orcid": "0000-0003-3616-6224"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1qg2fyz7nb8t5.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0361215",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712518/",
  "id": "1qg2fyz7nb8t5",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0361215",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Animal Cells"
    ],
    [
      "heading",
      "Animal Models"
    ],
    [
      "heading",
      "Animal Studies"
    ],
    [
      "heading",
      "Animals"
    ],
    [
      "heading",
      "Apoptosis"
    ],
    [
      "heading",
      "B Vitamins"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Caenorhabditis"
    ],
    [
      "heading",
      "Caenorhabditis Elegans"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "heading",
      "Cell Death"
    ],
    [
      "heading",
      "Cell Processes"
    ],
    [
      "heading",
      "Cellular Structures and Organelles"
    ],
    [
      "heading",
      "Cellular Types"
    ],
    [
      "heading",
      "Chemical Compounds"
    ],
    [
      "heading",
      "Chemistry"
    ],
    [
      "heading",
      "Cobalamins"
    ],
    [
      "heading",
      "Eukaryota"
    ],
    [
      "heading",
      "Experimental Organism Systems"
    ],
    [
      "heading",
      "Fluorescence Imaging"
    ],
    [
      "heading",
      "Genetics"
    ],
    [
      "heading",
      "Germ Cells"
    ],
    [
      "heading",
      "Imaging Techniques"
    ],
    [
      "heading",
      "Invertebrates"
    ],
    [
      "heading",
      "Lysosomes"
    ],
    [
      "heading",
      "Model Organisms"
    ],
    [
      "heading",
      "Mutation"
    ],
    [
      "heading",
      "Nematoda"
    ],
    [
      "heading",
      "OVA"
    ],
    [
      "heading",
      "Oocytes"
    ],
    [
      "heading",
      "Organic Chemistry"
    ],
    [
      "heading",
      "Organic Compounds"
    ],
    [
      "heading",
      "Organisms"
    ],
    [
      "heading",
      "Physical Sciences"
    ],
    [
      "heading",
      "Point Mutation"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "Research and Analysis Methods"
    ],
    [
      "heading",
      "Substitution Mutation"
    ],
    [
      "heading",
      "Vitamins"
    ],
    [
      "heading",
      "Zoology"
    ],
    [
      "openalex",
      "2713|Autophagy in Disease and Therapy"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Apoptosis"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Lysosomes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Germ cells/Ova/Oocytes"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Mutation/Point mutation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Mutation/Substitution mutation"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Eukaryota/Animals/Invertebrates/Nematoda/Caenorhabditis/Caenorhabditis elegans"
    ],
    [
      "plos",
      "/Biology and life sciences/Zoology/Animals/Invertebrates/Nematoda/Caenorhabditis/Caenorhabditis elegans"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical compounds/Organic compounds/Vitamins/B vitamins/Cobalamins"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Organic chemistry/Organic compounds/Vitamins/B vitamins/Cobalamins"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Caenorhabditis elegans"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Caenorhabditis elegans"
    ],
    [
      "plos",
      "/Research and analysis methods/Imaging techniques/Fluorescence imaging"
    ],
    [
      "plos",
      "/Research and analysis methods/Model organisms/Caenorhabditis elegans"
    ]
  ],
  "openalex": "W7223851036",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0361215&type=printable",
  "pmcid": "PMC13712518",
  "pmid": "42945204",
  "published": "2026-10-27",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/1qg2fyz7nb8t5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.1371/journal.pone.0361215",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0361215"
    },
    {
      "first_seen": "2026-10-31T12:23:04Z",
      "native_id": "PMC13712518",
      "source": "pmc",
      "url": "https://doi.org/10.1371/journal.pone.0361215"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    },
    {
      "field": "biology",
      "origin": "heading:Zoology",
      "subfield": "zoology-behaviour"
    },
    {
      "field": "chemistry",
      "origin": "heading:Organic Chemistry",
      "subfield": "organic"
    }
  ],
  "title": "A premature ovarian insufficiency-associated LMD-3 point mutation impairs protein stability and causes autophagic-lysosomal dysfunction in Caenorhabditis elegans",
  "title_text": "A premature ovarian insufficiency-associated LMD-3 point mutation impairs protein stability and causes autophagic-lysosomal dysfunction in Caenorhabditis elegans",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:04Z",
  "url": "https://research.draconitic.com/paper/1qg2fyz7nb8t5",
  "venue": "PLOS One",
  "versions": []
}