Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung

• Published in: Respiratory research Vol. 22; no. 1; p. 49
• Main Authors: Cuevas-Mora, Karina, Roque, Willy, Shaghaghi, Hoora, Gochuico, Bernadette R, Rosas, Ivan O, Summer, Ross, Romero, Freddy
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08-02-2021; BioMed Central; BMC
• Subjects: Adaptor Protein Complex 3 - genetics; Adaptor Protein Complex beta Subunits - genetics; Adults; Alveoli; AMP; AMP-activated protein kinase; Animals; Antibodies; Biosynthesis; CRISPR; Cristae; Deoxyribonucleic acid; Development and progression; DNA; Electron transport; Electron transport chain; Energy conservation; Epithelial cells; Epithelium; Fibrosis; Glycolysis; Health aspects; Hereditary diseases; Hermanski-Pudlak Syndrome - genetics; Hermanski-Pudlak Syndrome - pathology; Hermanski-Pudlak Syndrome - physiopathology; Hermansky-Pudlak syndrome; Homeostasis; Homeostasis - physiology; Infrared imaging systems; Kinases; Laboratories; Lung - pathology; Lung - physiopathology; Lung diseases; Lungs; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - physiology; Mitochondrial DNA; Pathogenesis; Protein folding; Proteins; Pulmonary Alveoli - pathology; Pulmonary Alveoli - physiopathology; Pulmonary fibrosis; Respiratory Mucosa - pathology; Respiratory Mucosa - physiopathology; Structural analysis; Structure-function relationships; Tricarboxylic acid cycle; United States; St Louis Missouri; United States > US
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-021-01640-z

Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood.
We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2).
We observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase.
In summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.