Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study

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’s skeletal muscle, liver, kidney, small intestine, and particularly in the di...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-05, Vol.22 (11), p.5598
Main Authors: Laine-Menéndez, Sara, Domínguez-González, Cristina, Blázquez, Alberto, Delmiro, Aitor, García-Consuegra, Inés, Fernández-de la Torre, Miguel, Hernández-Laín, Aurelio, Sayas, Javier, Martín, Miguel Ángel, Morán, María
Format: Article
Language:English
Subjects:
diaphragm
mitochondrial diseases
respiratory failure
thymidine kinase 2
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Summary: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’s 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 β-actin and loss of GAPDH and α-actin. MALDI-TOF/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient’s diaphragm tissue. The TK2-deficient patient’s 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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22115598