Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.

Authors

Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li

Published in

Science advances. Volume 12. Issue 33. Pages eaeh0657. Aug 14, 2026. Epub Aug 12, 2026.

Abstract

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 Caenorhabditis elegans. 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-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPR^mt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.

PMID:
42585340
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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