The European respiratory journal · 2026
Pleuroparenchymal fibroelastosis in a monogenic mitochondrial DNA depletion syndrome.
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von Hardenberg Sandra, Maier Pia, Christian Leonard, Das Anibh Martin, Neubert Lavinia, Ruwisch Jannik, Peters Katrin, Schramm Dirk, Griese Matthias, Skawran Britta, Eilers Marlies, Jonigk Danny, Junge Norman, Haghikia Aiden, Hegelmaier Tobias, Hofmann Winfried, Seeliger Benjamin, Renz Diane Miriam, Stalke Amelie, Hartmayer Lara, Duscha Alexander, Schulze Martin, DiDonato Nataliya, Prokisch Holger, Auber Bernd, Knudsen Lars, Schupp Jonas C, Schwerk Nicolaus
Аннотация
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.
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.