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Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease
Sandrina P. Correia, … , Anna Wedell, Anna Wredenberg
Sandrina P. Correia, … , Anna Wedell, Anna Wredenberg
Published September 17, 2024
Citation Information: JCI Insight. 2024;9(20):e178645. https://doi.org/10.1172/jci.insight.178645.
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Clinical Research and Public Health Metabolism

Quantitative proteomics of patient fibroblasts reveal biomarkers and diagnostic signatures of mitochondrial disease

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Abstract

BACKGROUND Mitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1 in 2,000–5,000 individuals. They are the most common form of IEM, but, despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed.METHODS We investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups. Clinical presentations were structured using human phenotype ontology terms, and mass spectrometry–based proteomics was performed on primary fibroblasts. Additionally, we integrated 6 patients carrying variants of uncertain significance (VUS) to test proteomics as a diagnostic expansion.RESULTS Proteomic profiles from patient samples could be classified according to their biochemical and genetic characteristics, with the expression of 5 proteins (GPX4, MORF4L1, MOXD1, MSRA, and TMED9) correlating with the disease cohort, thus acting as putative biomarkers. Pathway analysis showed a deregulation of inflammatory and mitochondrial stress responses. This included the upregulation of glycosphingolipid metabolism and mitochondrial protein import, as well as the downregulation of arachidonic acid metabolism. Furthermore, we could assign pathogenicity to a VUS in MRPS23 by demonstrating the loss of associated mitochondrial ribosome subunits.CONCLUSION We established mass spectrometry–based proteomics on patient fibroblasts as a viable and versatile tool for diagnosing patients with mitochondrial disease.FUNDING The NovoNordisk Foundation, Knut and Alice Wallenberg Foundation, Wellcome Centre for Mitochondrial Research, UK Medical Research Council, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children.

Authors

Sandrina P. Correia, Marco F. Moedas, Lucie S. Taylor, Karin Naess, Albert Z. Lim, Robert McFarland, Zuzanna Kazior, Anastasia Rumyantseva, Rolf Wibom, Martin Engvall, Helene Bruhn, Nicole Lesko, Ákos Végvári, Lukas Käll, Matthias Trost, Charlotte L. Alston, Christoph Freyer, Robert W. Taylor, Anna Wedell, Anna Wredenberg

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Figure 1

Cohort description and HPO terms in patient groups.

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Cohort description and HPO terms in patient groups.
Medical chart review...
Medical chart review revealed HPO terms associated with mitochondrial disease. (A) Localization of cohort groups relative to mitochondrial biological function, OXPHOS (CI and CIV), Proteolytic function (MtProt), Aminoacylation of tRNAs (MtARS), mtDNA transcription (MtGenExp), tRNAs modification (MtGenExp) and RNA translation (MtGenExp). (B) Chord diagram illustrating cohort genes of interest and their relationship with the groups as defined in the methods and results sections. Line width thickness is equivalent to number of times gene is represented in group. Other genes with variants identified in the cohort but not shown in the plot are UROD, DPYS, SLC6A17, and DHTKD1 (C) Prevalence of HPO term in patient group in percentage (%) (further described in Supplemental Data File 1). Number of cases in each group: CI (n = 18), MtProt (n = 8), MtGenExp (n = 20), MtARS (n = 9), CIV (n = 12) ‡, “Decreased mitochondrial ATP Production” is not an official HPO term.

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