The transcription factor SKN-1 drives lysosomal enlargement during aging to maintain function

Xinyu Wang, Huimin Liu, Xiaoman Wang, Ben Zhou, Haiqing Tang and Shanshan Pang

PLOS Biology, 2025, vol. 23, issue 12, 1-20

Abstract: Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes. Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.Lysosomes are important for cellular degradation and signal transduction, but exhibit functional decline and morphological changes during aging. This study shows that dysfunctional aging lysosomes undergo an enlargement process promoted by the transcription factor SKN-1 as a compensatory mechanism to sustain function.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3003540

DOI: 10.1371/journal.pbio.3003540

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