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Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling

Linlin Gu1, Ranu Surolia1, Jennifer L Larson-Casey1

  • 1Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Cell Death and Differentiation
|August 20, 2021
PubMed

Insights

Mitochondrial B-cell lymphoma-2 (Bcl-2) increases apoptosis resistance in lung macrophages, driving pulmonary fibrosis. Inhibiting Bcl-2 or its interaction with Cpt1a can resolve established fibrosis.

Area of Science:

  • Cell Biology
  • Immunology
  • Pulmonary Medicine

Background:

  • Pulmonary fibrosis progression involves apoptosis resistance in lung macrophages, but the underlying mechanisms are unclear.
  • The mitochondrial calcium uniporter (MCU) influences metabolic reprogramming and fibrosis, yet its role in macrophage apoptosis is not fully understood.

Purpose of the Study:

  • To investigate the mechanisms of apoptosis resistance in lung macrophages during idiopathic pulmonary fibrosis (IPF).
  • To explore the role of mitochondrial B-cell lymphoma-2 (Bcl-2) and its interaction with fatty acid metabolism in pulmonary fibrosis.

Main Methods:

  • Analysis of mitochondrial Bcl-2 levels in lung macrophages from IPF patients and wild-type (WT) mice.
  • Investigation of the interaction between Carnitine palmitoyltransferase 1a (Cpt1a) and Bcl-2 using dominant-negative MCU (DN-MCU) mice and bleomycin injury models.
  • Assessment of apoptosis and fibrosis development following Bcl-2 deletion or inhibition with ABT-199.

Main Results:

  • Mitochondrial Bcl-2 was significantly increased in lung macrophages from IPF subjects and WT mice, but decreased in DN-MCU mice.
  • Carnitine palmitoyltransferase 1a (Cpt1a) directly interacted with Bcl-2's BH3 domain, anchoring it in mitochondria and inhibiting apoptosis.
  • A positive correlation between CPT1A and Bcl-2 was observed in IPF macrophages; disruption of this interaction induced apoptosis.
  • Bcl-2 deletion or inhibition protected mice from developing pulmonary fibrosis and resolved established fibrosis.

Conclusions:

  • Increased mitochondrial Bcl-2, mediated by Cpt1a-driven fatty acid oxidation, promotes apoptosis resistance in lung macrophages.
  • This interplay between fatty acid metabolism, apoptosis resistance, and mitochondrial calcium regulation is a key driver of pulmonary fibrosis.
  • Targeting the Cpt1a-Bcl-2 interaction offers a potential therapeutic strategy for pulmonary fibrosis.

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