OP-09 - Oxidized protein homeostasis: implication of circadian rhythm, oxidative stress and ageing

Abstract

A hallmark of ageing both at the cellular and organismal level is the accumulation of oxidatively damaged proteins. Failure of protein maintenance is a major contributor to the age-associated accumulation of damaged proteins (Baraibar and Friguet, 2012, Prog Mol Biol Transl Sci 109: 249-75; Chondrogianni et al., 2014, Mol Asp Med 35:1-71). The circadian system orchestrates the timing of physiological processes of an organism living in daily environmental changes. Disruption of circadian rhythmicity has been shown to result in increased oxidative stress and accelerated ageing. Hence, we have investigated whether oxidized proteins levels and proteasome activities would exhibit circadian rhythmicity in synchronized cultured cells and addressed the mechanisms underlying this process (Desvergne et al., 2016, Free Radic Biol Med. 94:195-207). Using synchronized human embryonic kidney HEK 293 cells and primary dermal fibroblasts, we have shown that the levels of carbonylated protein and proteasome activity vary rhythmically following a 24 hours period. Such a modulation of proteasome activity is explained, at least in part, by the circadian expression of both Nrf2 and the proteasome activator PA28αβ. Finally, in contrast to young fibroblasts, no circadian modulation of the proteasome activity and carbonylated protein levels was evidenced in senescent fibroblasts.