Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study

International Journal of Molecular Sciences

Aurelio Hernández-Laín¹  Javier Sayas²  Miguel Fernández-de la Torre³  Inés García-Consuegra³  MiguelÁngel Martín³  Sara Laine-Menéndez³  María Morán³  Cristina Domínguez-González³  Aitor Delmiro³  Alberto Blázquez³ 

[1] Department of Pathology (Neuropathology), Hospital 12 de Octubre, 28041 Madrid, Spain;Department of Pneumology, Ventilation Unit, Hospital 12 de Octubre, 28041 Madrid, Spain;Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital ‘12 de Octubre’ (‘imas12’), 28041 Madrid, Spain;

关键词: mitochondrial diseases;    diaphragm;    thymidine kinase 2;    respiratory failure;   

DOI  :  10.3390/ijms22115598

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown