Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis.

Gazdhar, Amiq Ur Rahman; Lebrecht, Dirk; Roth, M; Tamm, Michael; Venhoff, Nils; Foocharoen, Chingching; Geiser, Thomas; Walker, Ulrich A (2014). Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis. Scientific Reports, 4, p. 5336. Nature Publishing Group 10.1038/srep05336

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Reactive oxygen species (ROS) have been implemented in the etiology of pulmonary fibrosis (PF) in systemic sclerosis. In the bleomycin model, we evaluated the role of acquired mutations in mitochondrial DNA (mtDNA) and respiratory chain defects as a trigger of ROS formation and fibrogenesis. Adult male Wistar rats received a single intratracheal instillation of bleomycin and their lungs were examined at different time points. Ashcroft scores, collagen and TGFβ1 levels documented a delayed onset of PF by day 14. In contrast, increased malon dialdehyde as a marker of ROS formation was detectable as early as 24 hours after bleomycin instillation and continued to increase. At day 7, lung tissue acquired significant amounts of mtDNA deletions, translating into a significant dysfunction of mtDNA-encoded, but not nucleus-encoded respiratory chain subunits. mtDNA deletions and markers of mtDNA-encoded respiratory chain dysfunction significantly correlated with pulmonary TGFβ1 concentrations and predicted PF in a multivariate model.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)

UniBE Contributor:

Gazdhar, Amiq Ur Rahman; Tamm, Michael and Geiser, Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Rahel Holderegger

Date Deposited:

10 Mar 2015 16:45

Last Modified:

24 Nov 2015 10:23

Publisher DOI:

10.1038/srep05336

PubMed ID:

24939573

BORIS DOI:

10.7892/boris.64357

URI:

https://boris.unibe.ch/id/eprint/64357

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