Pleuroparenchymal fibroelastosis in a monogenic mitochondrial DNA depletion syndrome
Year: 2026
Type: article
Study design: Case Report
Abstract: BACKGROUND: ) 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: -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: 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.
Source: European Respiratory Journal
Authors: Sandra von Hardenberg, Pia Maier, Leonard Christian, Anibh Martin Das, Lavinia Neubert, Jannik Ruwisch, Katrin Peters, Dirk Schramm, Matthias Griese, Britta Skawran, Marlies Eilers, Danny Jonigk, Norman Junge, Aiden Haghikia, Tobias Hegelmaier, Winfried Hofmann, Benjamin Seeliger, Diane Miriam Renz, Amelie Stalke, Lara Hartmayer, Alexander Duscha, Martin Schulze, Nataliya DiDonato, Holger Prokisch, Bernd Auber, Lars Knudsen, Jonas C. Schupp, Nicolaus Schwerk
Institutions: Medizinische Hochschule Hannover, German Center for Lung Research, LVR-Klinik für Orthopädie Viersen, Ludwig-Maximilians-Universität München, Integrated Oncology (United States), Universitätsklinikum Aachen, RWTH Aachen University, Helmholtz Munich, Institut für Humangenetik, Technical University of Munich, Yale University, Fraunhofer Institute for Toxicology and Experimental Medicine
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G2095453516, G2214017491, G6383367346
OpenAlex ID: W7221448907
FWCI:
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