{
  "abstract": "The ClpXP ATP-dependent unfoldase-protease complex plays important roles in maintaining protein homeostasis in the mitochondria. Pathogenic variants of CLPP have been identified in patients with Perrault syndrome type 3 (PRLTS3), a rare recessive mitochondrial disease characterized by sensorineural hearing loss, ovarian dysfunction, and neurological abnormalities. However, it remains unclear how these ClpP variants cause this disease. Here we identify three cellular substrates of ClpXP using proteomic analysis of PRLTS3 patient-derived fibroblasts, with follow up studies using induced pluripotent stem cells (iPSCs) and iPSC-derived neural progenitor cells, alongside in vitro biochemical assays. These substrates are: CHCHD2, a bi-organellar regulator of oxidative phosphorylation and mitochondrial stress responses; ALAS1, which catalyzes the rate-limiting step in heme biosynthesis; and TFAM, an essential mitochondrial transcription factor. Efficient degradation of these substrates by ClpXP requires the adaptor protein PDIP38. We propose that dysregulated cellular levels of these substrates might contribute to the etiology of PRLTS3.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry, University of Toronto, Toronto, ON Canada",
    "Mitochondrial Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK",
    "Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK",
    "Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK",
    "Division of Molecular and Cellular Function, School of Biological Sciences, The University of Manchester, Manchester, UK",
    "Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK",
    "NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK",
    "Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK",
    "Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland",
    "Department of Chemistry, University of Toronto, Toronto, ON Canada"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Mazen E. Aljghami",
      "orcid": "0009-0003-2990-1873"
    },
    {
      "affs": [
        0
      ],
      "name": "Trevor M. Morey"
    },
    {
      "affs": [
        0
      ],
      "name": "Mark F. Mabanglo"
    },
    {
      "affs": [
        1
      ],
      "name": "Jonathan J. Meyrick",
      "orcid": "0000-0003-1193-7125"
    },
    {
      "affs": [
        2
      ],
      "name": "Huw B. Thomas",
      "orcid": "0000-0001-9626-9706"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiacheng Yu",
      "orcid": "0009-0000-2588-0428"
    },
    {
      "affs": [
        0
      ],
      "name": "Arveen Tahmasebi"
    },
    {
      "affs": [
        2
      ],
      "name": "King Lam Lai"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Benjamin Bernard Armando Raymond",
      "orcid": "0000-0003-3610-9289"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Matthias Trost"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Robert W. Taylor",
      "orcid": "0000-0002-7768-8873"
    },
    {
      "affs": [
        2
      ],
      "name": "Raymond T. O’Keefe",
      "orcid": "0000-0001-8764-1289"
    },
    {
      "affs": [
        2,
        7
      ],
      "name": "William G. Newman",
      "orcid": "0000-0002-6382-4678"
    },
    {
      "affs": [
        1,
        8
      ],
      "name": "Uwe Richter"
    },
    {
      "affs": [
        0,
        9
      ],
      "name": "Walid A. Houry",
      "orcid": "0000-0002-1861-3441"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dpmw53sm1w2p9.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-77888-0",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13696721/",
  "id": "dpmw53sm1w2p9",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-77888-0",
  "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",
      "Article"
    ],
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      "openalex",
      "1312|Mitochondrial Function and Pathology"
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  "openalex": "W7214238069",
  "pdf_url": "https://europepmc.org/articles/PMC13696721?pdf=render",
  "pmcid": "PMC13696721",
  "pmid": "42928091",
  "published": "2026-09-24",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/dpmw53sm1w2p9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:01Z",
      "native_id": "PMC13696721",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41467-026-77888-0"
    },
    {
      "first_seen": "2026-10-30T12:21:18Z",
      "native_id": "MED:42928091",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42928091"
    }
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Mitochondrial Function and Pathology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome",
  "title_text": "Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:34:00Z",
  "url": "https://research.draconitic.com/paper/dpmw53sm1w2p9",
  "venue": "Nature Communications",
  "versions": []
}