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Adv."],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>\n                    Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in\n                    <jats:italic toggle=\"yes\">Caenorhabditis elegans<\/jats:italic>\n                    . Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion\u2013ELT-2\u2013lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPR\n                    <jats:sup>mt<\/jats:sup>\n                    ) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress\u2013induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2\u2013dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh0657","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:01:07Z","timestamp":1786557667000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Mitochondrial stress activates ELT-2\u2013dependent lysosomal proteostasis to extend lifespan in\n                    <i>C. elegans<\/i>"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-0378","authenticated-orcid":true,"given":"Rendan","family":"Yang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Reproductive Medicine Center, Zhongshan Hospital, Obstetrics &amp; 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