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Adv."],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:p>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-\u03b3 (IFN-\u03b3)\u2013 and interleukin-4 (IL-4)\/IL-13\u2013stimulated 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)\u2013dependent 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)\u2013dependent 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\u2013mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4\/IL-13 response.<\/jats:p>","DOI":"10.1126\/sciadv.aed6318","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:59:26Z","timestamp":1787162366000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial profiling across macrophage states reveals inhibition of IL-4\/IL-13 reprogramming by the integrated stress response"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7384-320X","authenticated-orcid":true,"given":"Joan","family":"Blanco-Fernandez","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, 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