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von Hardenberg, S.* ; Maier, P.* ; Christian, L.* ; Das, A.M.* ; Neubert, L.* ; Ruwisch, J.* ; Peters, K.* ; Schramm, D.* ; Griese, M.* ; Skawran, B.* ; Eilers, M.* ; Jonigk, D.* ; Junge, N.* ; Haghikia, A.* ; Hegelmaier, T.* ; Hofmann, W.* ; Seeliger, B.* ; Renz, D.M.* ; Stalke, A.* ; Hartmayer, L.* ; Duscha, A.* ; Schulze, M.* ; DiDonato, N.* ; Prokisch, H. ; Auber, B.* ; Knudsen, L.* ; Schupp, J.C.* ; Schwerk, N.*

Pleuroparenchymal fibroelastosis in a monogenic mitochondrial DNA depletion syndrome.

Eur. Respir. J., DOI: 10.1183/13993003.00791-2026 (2026)
Postprint DOI PMC
Open Access Green
BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare, most often idiopathic fibrotic lung disease with poor prognosis, mainly affecting adults. Biallelic pathogenic variants in the deoxyguanosine kinase gene (DGUOK) cause a mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological disease. Neither detailed pulmonary manifestations nor a pulmonary-dominant phenotype has been reported. METHODS: We describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single-nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy, respiratory chain enzyme activity assays and mtDNA recovery experiment were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing data. RESULTS: All patients (ages 5-36 years) carried biallelic pathogenic DGUOK variants, including an unreported intronic alteration in seven. All presented with progressive dyspnea, weight loss and some with pneumothoraces. Chest computed tomography and lung biopsies demonstrated features of PPFE. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells at the fibrotic edge, together with a transcriptional signature of nuclear DNA damage response. Ultrastructural analysis confirmed mitochondrial abnormalities in alveolar type 2 and Aberrant Basaloid cells. CONCLUSION: This study provides evidence that mitochondrial dysfunction can contribute to early-onset PPFE independent of age, with a DNA damage response signature in aberrant epithelial cell populations previously described only in adult fibrotic lung disease. DGUOK deficiency and other hereditary mitochondrial disorders should be considered in children and young adults presenting with PPFE of unknown origin.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0903-1936
e-ISSN 1399-3003
Zeitschrift European Respiratory Journal
Verlag European Respiratory Society
Verlagsort Sheffield
Begutachtungsstatus Peer reviewed
Institut(e) Institiute of Neurogenomics (ING)