11 March 2021 - 11 March 2021
1:00PM - 2:00PM
The Biosciences department runs two seminar series: Departmental seminars that cover a wide range of biological topics, and EEE seminars that cover topics related to Ecology, Evolution and Environment.
Host: David Weinkove
The age-related failure of protein homeostasis (proteostasis collapse) is a highly conserved phenomenon that affects all tissues and underlies susceptibility to a wide range of age-associated diseases. Despite this, the processes that determine the timing and magnitude of proteostasis collapse with age remain obscure. We have recently demonstrated that in the nematode worm Caenorhabditis elegans, down-tuning respiration during development potently suppresses proteostasis collapse in adulthood. However, it is unknown how these beneficial effects are mediated. In this seminar, I will provide evidence that in response to developmental electron transport chain impairment, mitochondria shift the composition of the cytosolic protein quality control network from a predominantly “folding-based” strategy, towards a “holdase-centric” approach in early adulthood, thereby protecting against age-related protein aggregation. This response is achieved through the PP2A complex, which generates a dephosphorylated variant of the transcription factor HSF-1 in response to mitochondrial stress. This tailors HSF1 activity such that genes encoding for small heat shock proteins are preferentially expressed. We find that the Mitochondria-PP2A-HSF1 transcriptional axis is also present in human cells and propose that this mechanism exists to more efficiently protect the proteome under conditions of limited ATP availability. Our work suggests that mitochondrial function is intimately coupled with the timing and severity of age-related changes in cytosolic proteostasis, and that by identifying methods to activate mitochondria-to-cytosolic protein quality control pathways, it may be possible to ameliorate protein conformational diseases and delay ageing.
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