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In particular, the heat shock response facilitates the upregulation of molecular chaperones and protein remodeling factors that mediate proteostasis in response to accumulated misfolded proteins in the nucleus and cytosol. However, in response to stress neurons struggle to induce a canonical heat shock response, highlighting our poor understanding of how neurons maintain proteostasis. Specifically, the ability of post-mitotic respiring cells to regulate the heat shock response in comparison to their rapidly dividing, predominantly glycolytic counterparts has been under-studied. In this study, we employ yeast models that are easily manipulated to generate energy via glycolysis or mitochondrial respiration by changing the carbon source in the media. Using this model, we demonstrate that Hsf1 activity, the heat shock response and proteostasis are impaired in respiring cells. Interestingly, our data show that reduced Hsf1 activity regulates viability of respiring cells, with respiring cells poorly tolerating constitutively activated Hsf1. Finally, we describe alternative post-translational programming of the molecular chaperones Hsp70 and Hsp104 that plausibly enables respiring cells to mediate proteostasis despite a dampened heat shock response. Our findings offer new insights into possible proteostatic strategies employed by cells in different metabolic conditions.<\/jats:p>","DOI":"10.64898\/2026.05.07.723568","type":"posted-content","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T13:55:14Z","timestamp":1778507714000},"source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial respiration modulates Hsf1 activation and the heat shock response"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6073-5826","authenticated-orcid":false,"given":"D.W.","family":"McDonald","sequence":"first","affiliation":[{"name":"Department of Biology, The University of Western Ontario, London, ON, N6A 3K7, Canada"},{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, N6A 3K7, 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