{
  "abstract": "Purpose: RP is the most common inherited retinal dystrophy. Limited understanding of how diverse genetic defects converge to cause photoreceptor degeneration hinders the development of mutation-agnostic therapies. Although intracellular Ca²⁺ dysregulation is an early hallmark across genetic variants, its mechanistic link to photoreceptor degeneration remains unclear. This study investigated whether plasma membrane calcium ATPases (PMCA)–mediated Ca²⁺ extrusion induces cytoplasmic acidification that contributes to photoreceptor death in two mouse models of RP.\n\nMethods: PMCA expression (immunofluorescence, RT-qPCR), cytoplasmic acidification (LysoTracker Red [LTR] staining), ultrastructural changes (electron microscopy), calpain-2 activity (in situ zymography) and cell death (TUNEL) were assessed in RP mouse retinas. PMCA-mediated acidification was validated in wild-type (WT) retinal explants under ionophore-induced Ca²⁺ overload. Neuroprotection by PMCA inhibition was evaluated ex vivo (retinal explants) and in vivo (intravitreal injection) by histological photoreceptor preservation.\n\nResults: Retinas from rd10 and homozygous P23H mice exhibited cytoplasmic acidification respect to WT. During the early stages of degeneration, the proportion of acidified photoreceptors (LTR-positive) exceeded that of TUNEL-positive photoreceptors, with LTR staining appearing before the onset of TUNEL labeling. Acidification correlated with PMCA upregulation. Ionophore-induced Ca²⁺ overload recapitulated cytoplasmic acidification ex vivo in WT retinas, which was prevented by PMCA inhibition. In rd10 mice, PMCA inhibition preserved photoreceptors ex and in vivo at different stages.\n\nConclusions: Our findings identify PMCA as a key mediator of pathological cytoplasmic acidification in RP and improve understanding of mechanisms underlying photoreceptor degeneration, which may facilitate the development of mutation-independent therapies and stage-specific interventions for RP progression.",
  "abstract_shown": true,
  "affiliations": [
    "Centro de Investigaciones Biológicas Margarita Salas (CSIC), Madrid, Spain",
    "Cell Biology and Pathology Department, University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Institute of Neurosciences of Castilla y León (INCYL), Salamanca, Spain",
    "Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, Spain",
    "Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) ISCIII, Madrid, Spain"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Alberto M. Hernández-Pinto"
    },
    {
      "affs": [
        0
      ],
      "name": "Natalia Rodríguez-Muela"
    },
    {
      "affs": [
        0
      ],
      "name": "Noelia Pimentel-Mayordomo"
    },
    {
      "affs": [
        0
      ],
      "name": "Patricia Boya"
    },
    {
      "affs": [
        1
      ],
      "name": "Concepción Lillo"
    },
    {
      "affs": [
        2
      ],
      "name": "Almudena Sacristán-Reviriego"
    },
    {
      "affs": [
        0
      ],
      "name": "Enrique J. de la Rosa"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Catalina Hernández-Sánchez"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c1zvjs2yj55d5.bib",
  "cited_by": 0,
  "doi": "10.1167/iovs.67.12.60",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13715910/",
  "id": "c1zvjs2yj55d5",
  "issns": [
    "0146-0404",
    "1552-5783"
  ],
  "landing_url": "https://doi.org/10.1167/iovs.67.12.60",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Retina"
    ],
    [
      "openalex",
      "1312|Retinal Development and Disorders"
    ]
  ],
  "openalex": "W7223363180",
  "pdf_url": null,
  "pmcid": "PMC13715910",
  "pmid": "42924989",
  "published": "2026-10-23",
  "publisher": "Association for Research in Vision and Ophthalmology",
  "ris": "https://research.draconitic.com/paper/c1zvjs2yj55d5.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:23:05Z",
      "native_id": "PMC13715910",
      "source": "pmc",
      "url": "https://doi.org/10.1167/iovs.67.12.60"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Retinal Development and Disorders",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Plasma Membrane Calcium ATPases Drive Cytoplasmic Acidification and Photoreceptor Degeneration in Retinitis Pigmentosa",
  "title_text": "Plasma Membrane Calcium ATPases Drive Cytoplasmic Acidification and Photoreceptor Degeneration in Retinitis Pigmentosa",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:23:05Z",
  "url": "https://research.draconitic.com/paper/c1zvjs2yj55d5",
  "venue": "Investigative Ophthalmology & Visual Science",
  "versions": []
}