{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T11:38:52Z","timestamp":1761824332747,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Ministry of Education and Research Germany","award":["01GM1920"],"award-info":[{"award-number":["01GM1920"]}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["01GM1906A"],"award-info":[{"award-number":["01GM1906A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003981","name":"Agenzia Spaziale Italiana","doi-asserted-by":"publisher","award":["DC-VUM-2017-006"],"award-info":[{"award-number":["DC-VUM-2017-006"]}],"id":[{"id":"10.13039\/501100003981","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly understood. Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX) activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene expression analysis. To gain molecular insight into the pathogenesis, we applied network and pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber transcriptome. We then integrated our results with proteomics data that we previously obtained comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of the combination of LCM and a multi-omics approach, we here provide a comprehensive resource to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts involved in translational elongation and protein synthesis. Furthermore, based on functional annotation analysis, we find that mitochondrial transcripts are the most enriched among those with significantly different expression between COX-positive and COX-negative fibers, indicating that our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrichments include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of post-transcriptional mechanisms in shaping this disease phenotype.<\/jats:p>","DOI":"10.3390\/ijms222011080","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T09:10:49Z","timestamp":1634202649000},"page":"11080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers"],"prefix":"10.3390","volume":"22","author":[{"given":"Matthias","family":"Elstner","sequence":"first","affiliation":[{"name":"Department of Neurology, Technical University Munich, 81675 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konrad","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Center for Addictive Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, 8001 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-6286","authenticated-orcid":false,"given":"Holger","family":"Prokisch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany"},{"name":"Institute of Neurogenomics, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-4652","authenticated-orcid":false,"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedrich-Baur-Institute, University of Munich, 80336 Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), 81675 Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), 81675 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6244-3358","authenticated-orcid":false,"given":"Marta","family":"Murgia","sequence":"additional","affiliation":[{"name":"Department of Proteomics a Signal Transduction, Max Planck Institute of Biochemistry, 82352 Martinsried, Germany"},{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/path.4809","article-title":"The genetics and pathology of mitochondrial disease","volume":"241","author":"Alston","year":"2017","journal-title":"J. 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