Aman, Yahyah; Erinjeri, Annmary Paul; Tataridas-Pallas, Nikolaos; Williams, Rhianna; Wellman, Rachel; Chapman, Hannah; Labbadia, John; (2022) Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors. Cell Reports , 41 (8) , Article 111690. 10.1016/j.celrep.2022.111690.

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Abstract

The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.

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