Fibrosis as a Disease of Aging and Mitochondrial Dysfunction

Despite the fact that Idiopathic Pulmonary Fibrosis (IPF) is a fatal and progressive lung disease of unknown etiology, few new patho-biologic models have emerged. Repetitive injury of mitochondrial-enriched type II alveolar epithelial cells (AECII) appears to be a key triggering event that leads to fibrosis, which is linked to a secretion of pro-fibrotic cytokines and increased apoptosis. Although AECII contain approximately 50% of the lung mitochondrial mass, the role of mitochondria in IPF pathobiology is unknown. We recently discovered that AECII from human IPF lungs have an accumulation of dysmorphic and dysfunctional mitochondria associated with very low expression of the crucial protective protein involved in mitochondrial homeostasis, PTEN-induced putative kinase 1 (PINK1). Low expression of PINK1 is associated with ER stress and aging, leading to increased susceptibility to cell apoptosis and fibrosis. However, no information is available how ER stress regulates PINK1 expression and how loss of PINK1 activates pro-fibrotic responses. Our novel studies suggest that the ER stress induces a transcriptional repressor that negatively regulates PINK1 gene expression, and reduced PINK1 levels. Low expression of PINK1 leads to mitochondrial depolarization, apoptosis, and release of damage associated molecular pattern that activate pro-fibrotic responses. Our studies bring forth a unique molecular model linking mitochondrial dysfunction and fibrosis that sets the stage for identifying novel links of aging and fibrosis and therapeutic targets.

Mitochondrial Homeostasis and Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and mean pulmonary arterial pressure leading to dysfunction of the right ventricle, reduced cardiac output and death. Vascular remodeling is characterized by obstructive vascular lesions of the distal pulmonary arteries due in part to excessive injury and apoptosis of endothelial cells and proliferation of the pulmonary artery smooth muscle cells (PASMCs).  Mitochondria dysregulation is intimately related with the etiology of PAH. We are investigating the potential role of dysregulated mitochondrial homeostasis in endothelial vulnerability to injury and PASMCs proliferation using unique animal models of PAH, novel hemodynamic assessments in rodents of pulmonary hypertension and heart function, and lung cells derived from PAH patients.

PINK1 and mtDNA metabolism

The mitochondrial genome is 16.5 kb and mechanisms to maintain their replication, translation, and repair are not completely understood. A reduction in mitochondrial DNA (mtDNA) replication and/or transcription may contribute to impaired mitochondrial oxidative phosphorylation, or accumulation of mtDNA mutations may affect mtDNA replication and transcription. We are studying in collaboration with Dr. Brett Kaufman whether PINK1 regulates mtDNA metabolism by regulation of TFAM, the principal packaging and key transcription factor of mtDNA, and the function of mtDNA repair enzymes.