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Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia
Friedreich’s ataxia (FRDA) is a severe multisystemic disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a m...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10644315/ https://www.ncbi.nlm.nih.gov/pubmed/38027498 http://dx.doi.org/10.3389/fnins.2023.1289027 |
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author | Indelicato, Elisabetta Faserl, Klaus Amprosi, Matthias Nachbauer, Wolfgang Schneider, Rainer Wanschitz, Julia Sarg, Bettina Boesch, Sylvia |
author_facet | Indelicato, Elisabetta Faserl, Klaus Amprosi, Matthias Nachbauer, Wolfgang Schneider, Rainer Wanschitz, Julia Sarg, Bettina Boesch, Sylvia |
author_sort | Indelicato, Elisabetta |
collection | PubMed |
description | Friedreich’s ataxia (FRDA) is a severe multisystemic disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled in vivo to address open questions on FRDA pathophysiology. Thus, we performed a quantitative mass spectrometry-based proteomics analysis in gastrocnemius skeletal muscle biopsies from genetically confirmed FRDA patients (n = 5) and controls. Obtained data files were processed using Proteome Discoverer and searched by Sequest HT engine against a UniProt human reference proteome database. Comparing skeletal muscle proteomics profiles between FRDA and controls, we identified 228 significant differentially expressed (DE) proteins, of which 227 were downregulated in FRDA. Principal component analysis showed a clear separation between FRDA and control samples. Interactome analysis revealed clustering of DE proteins in oxidative phosphorylation, ribosomal elements, mitochondrial architecture control, and fission/fusion pathways. DE findings in the muscle-specific proteomics suggested a shift toward fast-twitching glycolytic fibers. Notably, most DE proteins (169/228, 74%) are target of the transcription factor nuclear factor-erythroid 2. Our data corroborate a mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and a likely adaptive metabolic shift of contractile proteins. The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle-omics as disease state readout in FRDA. |
format | Online Article Text |
id | pubmed-10644315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106443152023-01-01 Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia Indelicato, Elisabetta Faserl, Klaus Amprosi, Matthias Nachbauer, Wolfgang Schneider, Rainer Wanschitz, Julia Sarg, Bettina Boesch, Sylvia Front Neurosci Neuroscience Friedreich’s ataxia (FRDA) is a severe multisystemic disorder caused by a deficiency of the mitochondrial protein frataxin. While some aspects of FRDA pathology are developmental, the causes underlying the steady progression are unclear. The inaccessibility of key affected tissues to sampling is a main hurdle. Skeletal muscle displays a disease phenotype and may be sampled in vivo to address open questions on FRDA pathophysiology. Thus, we performed a quantitative mass spectrometry-based proteomics analysis in gastrocnemius skeletal muscle biopsies from genetically confirmed FRDA patients (n = 5) and controls. Obtained data files were processed using Proteome Discoverer and searched by Sequest HT engine against a UniProt human reference proteome database. Comparing skeletal muscle proteomics profiles between FRDA and controls, we identified 228 significant differentially expressed (DE) proteins, of which 227 were downregulated in FRDA. Principal component analysis showed a clear separation between FRDA and control samples. Interactome analysis revealed clustering of DE proteins in oxidative phosphorylation, ribosomal elements, mitochondrial architecture control, and fission/fusion pathways. DE findings in the muscle-specific proteomics suggested a shift toward fast-twitching glycolytic fibers. Notably, most DE proteins (169/228, 74%) are target of the transcription factor nuclear factor-erythroid 2. Our data corroborate a mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and a likely adaptive metabolic shift of contractile proteins. The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle-omics as disease state readout in FRDA. Frontiers Media S.A. 2023-10-31 /pmc/articles/PMC10644315/ /pubmed/38027498 http://dx.doi.org/10.3389/fnins.2023.1289027 Text en Copyright © 2023 Indelicato, Faserl, Amprosi, Nachbauer, Schneider, Wanschitz, Sarg and Boesch. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Indelicato, Elisabetta Faserl, Klaus Amprosi, Matthias Nachbauer, Wolfgang Schneider, Rainer Wanschitz, Julia Sarg, Bettina Boesch, Sylvia Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia |
title | Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia |
title_full | Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia |
title_fullStr | Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia |
title_full_unstemmed | Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia |
title_short | Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia |
title_sort | skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in friedreich’s ataxia |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10644315/ https://www.ncbi.nlm.nih.gov/pubmed/38027498 http://dx.doi.org/10.3389/fnins.2023.1289027 |
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