Mitochondrial Transplantation: A Novel Therapy for Lung Fibrosis

Abstract

Chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) are prevalent among veterans and U.S. military personnel. IPF is a progressive, irreversible, and lethal disease with no effective treatment save for lung transplantation. IPF arises from relentless and extensive fibroproliferative injury, which itself stems from the inability of normal repair processes in the lung to deactivate following stimuli. The disease is characterized by focal zones of fibroblast proliferation. Transforming growth factor-Beta (TGF-Beta) plays a crucial role in fibrosis development, mediating cell activation, migration, and invasion. Increased TGF-Beta mediates metabolic reprogramming in cells involved in IPF progression, shifting bioenergetics from oxidative phosphorylation (OXPHOS) towards glycolysis. In fibroblasts and myofibroblasts, TGF-Beta increases expression of glycolytic enzymes and glucose transporters, as well as lactate production. In alveolar epithelial type II (AE2) cells, genes involved in metabolism are downregulated, and there is increased lactate production. A more glycolytic phenotype is also observed in alveolar macrophages in IPF. Decreased ATP production occurs in fibroblasts and myofibroblasts, while in IPF AE2 cells, fibroblasts, and macrophages, decreased electron transport chain (ETC) complex activity and lower oxygen consumption rates (OCR) have been observed. This work aims to deliver polymer-functionalized mitochondria to fibroblasts, AE2 cells, and macrophages in IPF lungs with the goal of restoring a favorable metabolic phenotype that can attenuate or reverse the disease. Our findings highlight that TGF- treatment of fibroblasts resulted in metabolic reprogramming towards glycolysis and a pro-fibrotic phenotype. We demonstrate that mitochondria coated with a Dextran-triphenlyphosphonium (Dextran-TPP) polymer were efficiently internalized by alveolar epithelial cells and fibroblasts.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 2020
Accession Number
AD1111606

Entities

People

  • Elvin Blanco

Organizations

  • Houston Methodist Research Institute

Tags

DTIC Thesaurus Topics

  • Biomedical Research
  • Cells
  • Confocal Microscopy
  • Disease Attributes
  • Diseases And Disorders
  • Dynamics
  • Electronic Mail
  • Epithelial Cells
  • Glycolysis
  • Growth Factors
  • Health Services
  • Lung Diseases
  • Macrophages
  • Medical Personnel
  • Metabolism
  • Military Personnel
  • Muscle Cells
  • Peptide Growth Factors
  • Phosphorylation
  • Rate Of Consumption
  • Therapy

Fields of Study

  • Biology

Readers

  • Immunology and Pathology
  • Molecular and Cellular Biology

Technology Areas

  • Biotechnology
  • Microelectronics