Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome
10 affiliations
- 1Department of Biochemistry, University of Toronto, Toronto, ON Canada
- 2Mitochondrial Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- 3Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK
- 4Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
- 5Division of Molecular and Cellular Function, School of Biological Sciences, The University of Manchester, Manchester, UK
- 6Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- 7NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- 8Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK
- 9Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
- 10Department of Chemistry, University of Toronto, Toronto, ON Canada
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.
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BibTeX
@article{aljghami2026identification,
title = {{Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome}},
author = {Mazen E. Aljghami and Trevor M. Morey and Mark F. Mabanglo and Jonathan J. Meyrick and Huw B. Thomas and Jiacheng Yu and Arveen Tahmasebi and King Lam Lai and Benjamin Bernard Armando Raymond and Matthias Trost and Robert W. Taylor and Raymond T. O’Keefe and William G. Newman and Uwe Richter and Walid A. Houry},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77888-0},
url = {https://doi.org/10.1038/s41467-026-77888-0},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Identification of substrates of the human mitochondrial ClpXP protease and its implications for Perrault syndrome
AU - Mazen E. Aljghami
AU - Trevor M. Morey
AU - Mark F. Mabanglo
AU - Jonathan J. Meyrick
AU - Huw B. Thomas
AU - Jiacheng Yu
AU - Arveen Tahmasebi
AU - King Lam Lai
AU - Benjamin Bernard Armando Raymond
AU - Matthias Trost
AU - Robert W. Taylor
AU - Raymond T. O’Keefe
AU - William G. Newman
AU - Uwe Richter
AU - Walid A. Houry
PY - 2026
DA - 2026/09/24
JO - Nature Communications
DO - 10.1038/s41467-026-77888-0
UR - https://doi.org/10.1038/s41467-026-77888-0
AB - 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.
SN - 2041-1723
ER -