Academic Journal
Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
| Τίτλος: | Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response. |
|---|---|
| Συγγραφείς: | Blanco-Fernandez J; Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland., Lisci M; Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland., Foged MM; Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland., Chapuis C; Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland., Pflästerer T; Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland., Kleele T; Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland., Jourdain AA; Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. |
| Πηγή: | Science advances [Sci Adv] 2026 Aug 21; Vol. 12 (34), pp. eaed6318. Date of Electronic Publication: 2026 Aug 19. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| Ιατρικοί όροι (MeSH): | Interleukin-13*/metabolism , Mitochondria*/metabolism , Mitochondria*/genetics , Interleukin-4*/metabolism , Macrophages*/metabolism , Macrophages*/cytology , Integrated Stress Response* , Cellular Reprogramming*, STAT6 Transcription Factor/metabolism ; DNA, Mitochondrial/genetics ; Proteomics/methods ; Interferon-gamma/pharmacology ; Lipopolysaccharides/pharmacology ; Animals ; Mice ; Membrane Potential, Mitochondrial ; Metabolic Reprogramming |
| Περίληψη: | Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response. |
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| Substance Nomenclature: | 0 (Interleukin-13) 207137-56-2 (Interleukin-4) 0 (STAT6 Transcription Factor) 0 (DNA, Mitochondrial) 82115-62-6 (Interferon-gamma) 0 (Lipopolysaccharides) |
| Entry Date(s): | Date Created: 20260819 Date Completed: 20260819 Latest Revision: 20260822 |
| Update Code: | 20260822 |
| PubMed Central ID: | PMC13488931 |
| DOI: | 10.1126/sciadv.aed6318 |
| PMID: | 42616903 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2375-2548 |
|---|---|
| DOI: | 10.1126/sciadv.aed6318 |