{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T14:53:27Z","timestamp":1769266407997,"version":"3.49.0"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T00:00:00Z","timestamp":1621900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III","award":["PMP15\/00025"],"award-info":[{"award-number":["PMP15\/00025"]}]},{"name":"Instituto de Salud Carlos III","award":["PI18\/01374"],"award-info":[{"award-number":["PI18\/01374"]}]},{"name":"Instituto de Salud Carlos III-The European Regional Development fund from the European Union","award":["PI17\/00093"],"award-info":[{"award-number":["PI17\/00093"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Our goal was to analyze postmortem tissues of an adult patient with late-onset thymidine kinase 2 (TK2) deficiency who died of respiratory failure. Compared with control tissues, we found a low mtDNA content in the patient\u2019s skeletal muscle, liver, kidney, small intestine, and particularly in the diaphragm, whereas heart and brain tissue showed normal mtDNA levels. mtDNA deletions were present in skeletal muscle and diaphragm. All tissues showed a low content of OXPHOS subunits, and this was especially evident in diaphragm, which also exhibited an abnormal protein profile, expression of non-muscular \u03b2-actin and loss of GAPDH and \u03b1-actin. MALDI-TOF\/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient\u2019s diaphragm tissue. The TK2-deficient patient\u2019s diaphragm showed a more profound loss of OXPHOS proteins, with lower levels of catalase, peroxiredoxin 6, cytosolic superoxide dismutase, p62 and the catalytic subunits of proteasome than diaphragms of ventilated controls. Strong overexpression of TK1 was observed in all tissues of the patient with diaphragm showing the highest levels. TK2 deficiency induces a more profound dysfunction of the diaphragm than of other tissues, which manifests as loss of OXPHOS and glycolytic proteins, sarcomeric components, antioxidants and overactivation of the TK1 salvage pathway that is not attributed to mechanical ventilation.<\/jats:p>","DOI":"10.3390\/ijms22115598","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T13:14:21Z","timestamp":1621948461000},"page":"5598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study"],"prefix":"10.3390","volume":"22","author":[{"given":"Sara","family":"Laine-Men\u00e9ndez","sequence":"first","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-988X","authenticated-orcid":false,"given":"Cristina","family":"Dom\u00ednguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"},{"name":"Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, 28029 Madrid, Spain"},{"name":"Deparment of Neurology, Neuromuscular Unit, Hospital 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Bl\u00e1zquez","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aitor","family":"Delmiro","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"Garc\u00eda-Consuegra","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Fern\u00e1ndez-de la Torre","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurelio","family":"Hern\u00e1ndez-La\u00edn","sequence":"additional","affiliation":[{"name":"Department of Pathology (Neuropathology), Hospital 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2399-4370","authenticated-orcid":false,"given":"Javier","family":"Sayas","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Ventilation Unit, Hospital 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-772X","authenticated-orcid":false,"given":"Miguel \u00c1ngel","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"},{"name":"Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5408-7189","authenticated-orcid":false,"given":"Mar\u00eda","family":"Mor\u00e1n","sequence":"additional","affiliation":[{"name":"Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigaci\u00f3n Sanitaria Hospital \u201812 de Octubre\u2019 (\u2018imas12\u2019), 28041 Madrid, Spain"},{"name":"Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/ng751","article-title":"Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy","volume":"29","author":"Saada","year":"2001","journal-title":"Nat. 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