Researchers from the DZL site BREATH have identified a previously unknown link between pathogenic variants in the DGUOK gene and the rare lung disease pleuroparenchymal fibroelastosis (PPFE). Their findings not only provide a possible explanation for previously unexplained cases but also offer new insights into the role of mitochondrial dysfunction in the development of pulmonary fibrosis.
When the Cause of Pulmonary Fibrosis Lies in the Mitochondria
Pleuroparenchymal fibroelastosis (PPFE) is a rare form of pulmonary fibrosis characterized by progressive scarring, particularly in the upper and peripheral regions of the lungs. The disease can lead to progressive shortness of breath, weight loss, and recurrent pneumothoraces. Its underlying cause often remains unknown. PPFE is associated with considerable morbidity and mortality, and no specific treatment options are currently available.
In a recent study, a research team led by PD Dr. Sandra v. Hardenberg (Institute of Human Genetics, MHH), Dr. Pia Maier (Department of Pediatric Pulmonology, Allergology and Neonatology), Prof. Dr. Jonas Schupp (Department of Respiratory Medicine and Infectious Diseases, MHH), and PD Dr. Nicolaus Schwerk (Department of Pediatric Pulmonology, Allergology and Neonatology) investigated nine patients with PPFE aged between five and 36 years. In all affected individuals, the researchers identified biallelic pathogenic variants in the DGUOK gene. This gene plays an important role in maintaining mitochondrial DNA and, consequently, mitochondrial function.
Until now, defects in the DGUOK gene have primarily been associated with severe mitochondrial disorders presenting in infancy, particularly affecting the liver and nervous system. The discovery that these defects can also manifest primarily as severe fibrotic lung disease in children, adolescents, and young adults significantly expands the known disease spectrum.
“For some patients whose rare pulmonary fibrosis previously had no identifiable cause, we can now provide a specific genetic explanation for the first time. This is important not only for diagnosis but also for enabling more targeted counseling for affected individuals and their families,” says BREATH PI PD Dr. Sandra v. Hardenberg.
Shared Mechanisms Across Different Fibrotic Lung Diseases
To better understand how these genetic alterations might contribute to lung damage, the research team analyzed lung tissue using single-nucleus RNA sequencing, among other methods. They identified so-called aberrant basaloid cells and their precursor cells at the sites of fibroalveolar remodeling.
These abnormal cell states are already known from idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases in adults. In this study, they were identified in fibrotic lung tissue from children for the first time. Electron microscopy additionally revealed structural abnormalities in the mitochondria.
“By analyzing lung tissue, we were able to link genetic alterations to differential gene expression profiles and their spatial distribution within the tissue. We also detected increased DNA double-strand breaks in alveolar type 2 cells, indicating cellular damage processes that may contribute to the development of aberrant basaloid cells,” explains Dr. Pia Maier, who conducts her research as a Clinician Scientist within the TITUS program.
The study thus links a clearly defined genetic cause to cellular alterations also observed in other forms of pulmonary fibrosis. Prof. Dr. Jonas Schupp, one of the senior authors of the study and head of the ILD specialist outpatient clinic at MHH, particularly emphasizes the shared cellular mechanisms underlying different fibrotic lung diseases. “This suggests that very different triggers may ultimately activate common pathological repair programs in the lungs. In the long term, identifying these shared mechanisms could help us discover new therapeutic targets for various fibrotic lung diseases,” explains the pulmonologist.
New Opportunities for Diagnosis and Research
The findings have immediate implications for diagnostic practice. Because pulmonary involvement in DGUOK-associated disease may previously have been overlooked or misclassified, the authors recommend genetic testing in cases of PPFE of unknown origin. “Especially in younger patients, this could help identify the underlying disease earlier and enable a more accurate diagnosis,” says PD Dr. Nicolaus Schwerk, pediatric pulmonologist at MHH and last author of the study.
At the same time, the significance of these findings extends beyond this rare patient population. The study provides evidence that impaired mitochondrial function can play a causal role in the development of pulmonary fibrosis. As a genetically well-defined disease, DGUOK-associated PPFE could therefore serve as a model for gaining a better understanding of fundamental mechanisms of fibrosis and investigating new therapeutic approaches.
There is currently no causal treatment available for the patients described in the study. However, identifying the underlying genetic defect represents an important step toward the future development of more targeted treatment strategies.
The BREATH scientists and authors of the study: Dr. Pia Maier, Prof. Dr. Jonas Schupp, PD Dr. Nicolaus Schwerk and PD Dr. Sandra von Hardenberg (from left to right)
