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

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.