A Pittsburgh School of Medicine research team examining cells sampled from the scar tissue in the lungs of patients with idiopathic pulmonary fibrosis (IPF) made a surprising discovery: misshapen, bloated mitochondria. This unexpected observation led to their conducting a study, published online this week, and which will be featured on the cover of the Journal of The American Society for Clinical Investigation‘s February issue. Results of this study could help explain for the first time why the older a person gets, the greater the risk of developing the deadly lung disease.

The Research Article entitled “PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis” ( Clin Invest. doi:10.1172/JCI74942) is coauthored by Ana L. Mora, Marta Bueno, Yen-Chun Lai, Judith Brands, Christelle Kamga, Catherine Corey, John Sembrat, Janet S. Lee, and Steve R. Duncan of the Vascular Medicine Institute and/or the Division of Pulmonary, Allergy and Critical Care Medicine, and The University of Pittsburgh in Pennsylvania; Yair Romero of the Faculty of Sciences at the Universidad Nacional Autnoma de Mexico, Ciudad Universitaria, Mexico City, Mexico; Claudette M. St. Croix of the University of Pittsburgh Center for Biological Imaging; Jose D. Herazo-Maya of the Pulmonary, Critical Care and Sleep Medicine at Yale School of Medicine, New Haven, Connecticut; Mauricio Rojas of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease; Sruti Shiva of the University of Pittsburgh Department of Pharmacology and Chemical Biology; and Charleen T. Chu of the University of Pittsburgh Department of Pathology.

The coauthors note that although increasing age has for some time been a known risk factor associated with development of idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms underlying the effects of advancing age had heretofore remained largely unexplained. While the etiology of some age-related neurodegenerative diseases have been associated with mitochondrial dysfunction, the Pitt-based research team’s that alveolar type II cells (AECIIs) in IPF patients’ the lungs reveal marked accumulation of misshapen and dysfunctional mitochondria. In turn, mitochondrial abnormalities in AECIIs of IPF patients’ lungs were associated with of ER stress marker upregulation, an observation recapitulated in normal mouse models with advancing age in response to ER stress stimulation.

After characterizing the oddities of the mitochondria, which provide energy for the cell, the research team measured levels of an enzyme called PTEN-induced putative kinase 1, or PINK1, that plays key roles in mitochondrial function and morphology. Experiments showed an association of mitochondrial impairment with reduced PINK1 expression. Mice deficient in PINK1 had dysfunctional, misshapen mitochondria in lung cells and were more susceptible to lung fibrosis development.

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The researchers report finding the mitochondrial impairment in IPF and aging lungs associated with diminished expression of PINK1, and that this PINK1 expression knockdown in epithelial lung cells causes mitochondrial depolarization and profibrotic factor expression. Additionally, young PINK1-deficient mice were observed developing similarly dysmorphic, dysfunctional mitochondria in the AECIIs, increasing their vulnerability to apoptosis and lung fibrosis development of. The researchers note that their data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, thereby promoting fibrosis in aging lungs, indicating that this deficiency is a significant risk factor for the development of IPF in people older than 75 years, who have 50 times higher IPF prevalence than people 35 years old or younger.

The coauthors note that mitochondria are particularly susceptible to age, with mitochondrial abnormalities often observed with aging, including enlargement, loss of cristae, destruction of inner membranes, swelling, and impaired respiration, and that interestingly, AECIIs in the lung are active progenitor and secretory cells with high energy demands, containing approximately 50% of lung mitochondrial mass.

“Although mitochondrial structure and function are understood to be regulated by ER stress and autophagic processes,” the coauthors observe, “to our knowledge, there have been no studies to date evaluating mitochondria in AECIIs in human IPF or in mouse models of IPF.” They conclude that the research team’s present findings indicate that aging and ER stress both have an important effect on the physiology of AECII mitochondria, and influence susceptibility to lung fibrosis.

“Older age is a well-known risk factor for IPF, a disease in which the lung tissue becomes progressively fibrotic, or scarred, leading to breathing difficulties and death within three to five years if a lung transplant isn’t possible,” says senior investigator Ana L. Mora, M.D. , assistant professor in the Division of Pulmonary, Allergy and Critical Care Medicine and a member of the Heart, Lung, Blood and Vascular Medicine Institute (VMI) at Pitt in a release. “The cause of the disease is unknown, or idiopathic.”

The central focus of Dr. Mora’s research is to develop greater understanding of the pathogenesis of Idiopathic Pulmonary Fibrosis. She has authored and co-authored more than 45 publications in peer review journals, reviews, editorials and book chapters, and her laboratory has been funded by NIH grants including as well as grants from the American Heart Association, and the American Lung Association. Dr Mora is member of the Southern Society of Investigation, the American Society of Immunologist, the American Society of Microbiology and the American Thoracic Society.

“The overall goal of our laboratory is to understand the pathogenesis of Idiopathic Pulmonary Fibrosis,” Dr. Mora notes. “We use animal models of lung fibrosis including bleomycin and the gammaherpesvirus infection and in vitro analyses of type II alveolar epithelial cells and alveolar macrophages to unveil molecular mechanisms involved in the host response to injury and repair.”

“Other chronic and progressive diseases we see with aging, such as Parkinson’s disease,” Dr. Mora continues, “have been recently associated with mitochondrial abnormalities, so we wondered if that was occurring in IPF. It was a simple question, but it hadn’t been asked before, so we examined lung cells from patients with advanced IPF and healthy people. We were so surprised to see dramatic differences in the number, shape and function of the mitochondria. We found also that low PINK1 is associated with increasing age and cellular stress [and] this might help explain why older people are at greater risk for developing IPF, and it could mean developing drugs that can boost PINK1 levels or improve mitochondrial function will help treat IPF.”

“These findings are remarkable as they identify a similar disease pathway to that seen in other age related brain diseases, comments Mark Gladwin, M.D., professor and chief of the Division of Pulmonary, Allergy and Critical Care Medicine, and Vascular Medicine Institute (VMI) director, who is not a member of the research team. “This is the first study to find that the mitochondria themselves, the energy factories of our cells, are altered with lung fibrosis.”

In addition to their mitochondrial and PINK1 observations, the Pitt research team hopes to find biomarkers that could identify the disease in its earlier stages and to explore other factors that could increase IPF susceptibility to.

This project was funded by National Institutes of Health grants NS065789 and AG026389; the Vascular Medicine Institute at the University of Pittsburgh, the Institute for Transfusion Medicine, and the Hemophilia Center of Western Pennsylvania.

The University of Pittsburgh Division of Pulmonary, Allergy, and Critical Care Medicine (PACCM) highlights robust research, education, and clinical patient care programs in Allergy, Pulmonary Disease and Critical Care Medicine. Acknowledging its commitment to respiratory disorders, PACCM was recently ranked 7th in the nation by US News and World Report.

Sources:
The University of Pittsburgh
The Journal of The American Society for Clinical Investigation

Image Credits:
The University of Pittsburgh