Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis

Abstract

Reactive oxygen species (ROS) are implicated in the aetiology of interstitial lung disease (ILD). We investigated the role of large-scale somatically acquired mutations in mitochondrial DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS-formation and lung fibrosis. Mitochondria were analysed in lung biopsies from 30 patients with idiopathic or connective tissue disease (CTD)-related ILD and 13 controls. In 17 patients we had paired biopsies from upper and lower lobes. Control samples were taken from lung cancer resections without interstitial fibrosis. Malondialdehyde, a marker of ROS-formation, was elevated in ILD-biopsies (p\u2009=\u20090.044). The activity of the mitochondrial respiratory chain (cytochrome c-oxidase/succinate dehydrogenase [COX/SDH]-ratio) was depressed in ILD (median\u2009=\u20090.10,) compared with controls (0.12, p\u2009<\u20090.001), as was the expression of mtDNA-encoded COX-subunit-2 protein normalized for the nucleus-encoded COX-subunit-4 (COX2/COX4-ratio; ILD-median\u2009=\u20090.6; controls\u2009=\u20092.2; p\u2009<\u20090.001). Wild-type mtDNA copies were slightly elevated in ILD (p\u2009=\u20090.088). The common mtDNA deletion was only present at low levels in controls (median\u2009=\u20090%) and at high levels in ILD (median\u2009=\u200917%; p\u2009<\u20090.001). In ILD-lungs with paired biopsies, lower lobes contained more malondialdehyde and mtDNA deletions than upper lobes and had lower COX2/COX4-ratios and COX/SDH-ratios (all p\u2009<\u20090.001). Acquired mtDNA-mutations and consecutive respiratory chain dysfunction may both trigger and perpetuate ROS-formation in ILD.