What question did this study set out to answer?

To investigate how myeloid TFAM influences mitochondrial stress, senescence, allergic inflammation, and the response to senolytic treatment.

May 13, 2026

Mitochondrial dysfunction due to myeloid TFAM loss limits senolytic efficacy in allergic airway inflammation

Key Points

To investigate how myeloid TFAM influences mitochondrial stress, senescence, allergic inflammation, and the response to senolytic treatment.
Induced allergic airway inflammation using dust mite, ragweed, and Aspergillus in TFAM-deficient mice and controls.
Assessed inflammation, remodeling, mitochondrial dysfunction, and senescence in vivo and in macrophage studies.
Evaluated senolytic therapy response with ABT-263 in macrophages and allergen-challenged mice.
TFAM deficiency worsened airway inflammation, eosinophilia, and increased markers of mitochondrial stress and senescence (exact metrics not provided).
TFAM-deficient macrophages had reduced mitochondrial mass and were more susceptible to senescence.
ABT-263 mitigated inflammation and eosinophilia in controls but failed to do so in TFAM-deficient mice.

Abstract

Abstract 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.

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