Mitochondrial dysfunction due to myeloid TFAM loss limits senolytic efficacy in allergic airway inflammation
Jackie Nguyen1, Courtney Van1, Zianne A Olverson2
1Pulmonary, Critical Care and Sleep Medicine, College of Medicine, The Ohio State University, OH, Columbus.
Rationale:
Macrophages are key drivers of allergic airway inflammation, but the mitochondrial mechanisms regulating these responses remain incompletely defined. Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA (mtDNA) maintenance and mitochondrial homeostasis.
Objectives:
To define the role of myeloid TFAM in mitochondrial stress, senescence, allergic airway inflammation, and response to senolytic therapy.
Methods:
Allergic airway inflammation was induced with dust mite, ragweed, and Aspergillus (DRA) in myeloid-specific TFAM-deficient mice TFAMfl/flLysMcre and littermate controls. Inflammatory, remodeling, mitochondrial, and senescence-associated outcomes were assessed in vivo and in macrophage-based mechanistic studies, including human alveolar macrophages. ABT-263 was used to evaluate senolytic responsiveness.
Measurements And Main Results:
Myeloid TFAM deficiency worsened DRA-induced airway inflammation, eosinophilia, goblet cell hyperplasia, and collagen deposition, and increased pulmonary inflammatory, cGAS-STING, and senescence-associated markers. TFAM-deficient macrophages showed reduced mitochondrial mass and mitochondrial gene expression, increased cytosolic mtDNA, and greater susceptibility to TGF-β-induced senescence. In human alveolar macrophages, IL-4 decreased TFAM expression and mtDNA content, increased cytosolic mtDNA, and induced senescence-associated genes. ABT-263 suppressed IL-4-induced senescence and inflammatory gene expression in macrophages and reduced eosinophilia and inflammatory mediator production in allergen-challenged control mice, but these effects were largely lost in TFAMfl/flLysMcre mice.
Conclusions:
Myeloid TFAM limits mtDNA stress, senescence-associated inflammation, and allergic airway pathology, and influences responsiveness to senolytic therapy.
Insights
Mitochondrial transcription factor A (TFAM) in myeloid cells limits allergic airway inflammation and senescence. TFAM deficiency worsens allergic responses and impairs senolytic therapy effectiveness.
Area of Science:
- Immunology
- Mitochondrial Biology
- Pulmonology
Background:
- Macrophages are central to allergic airway inflammation, but their mitochondrial regulation is unclear.
- Mitochondrial transcription factor A (TFAM) is crucial for maintaining mitochondrial DNA (mtDNA) and overall mitochondrial health.
Purpose of the Study:
- To investigate the role of myeloid TFAM in mitochondrial stress, cellular senescence, allergic airway inflammation, and response to senolytic treatments.
- To elucidate the mechanisms by which TFAM influences these processes in both mouse models and human cells.
Main Methods:
- Induced allergic airway inflammation using dust mite, ragweed, and Aspergillus (DRA) in myeloid-specific TFAM-deficient (TFAMfl/flLysMcre) mice and controls.
- Assessed inflammatory, remodeling, mitochondrial, and senescence markers in vivo and in vitro using human alveolar macrophages.
- Utilized ABT-263 to evaluate senolytic therapy responsiveness.
Main Results:
- Myeloid TFAM deficiency exacerbated DRA-induced airway inflammation, eosinophilia, goblet cell hyperplasia, and collagen deposition.
- TFAM-deficient macrophages exhibited reduced mitochondrial mass, decreased mitochondrial gene expression, increased cytosolic mtDNA, and heightened susceptibility to TGF-β-induced senescence.
- In human macrophages, IL-4 reduced TFAM and mtDNA, increased cytosolic mtDNA, and induced senescence; ABT-263's benefits were diminished in TFAM-deficient mice.
Conclusions:
- Myeloid TFAM plays a protective role by limiting mtDNA stress, senescence-associated inflammation, and allergic airway pathology.
- TFAM status significantly impacts the efficacy of senolytic therapy in the context of allergic airway inflammation.
