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
Summary
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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