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TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan

Perić, Matea; Lovrić, Anita; Šarić, Ana; Musa, Marina; Bou Dib, Peter; Rudan, Marina; Nikolić, Andrea; Sobočanec, Sandra; Mikecin, Ana-Matea; Dennerlein, Sven; Milošević, Ira; Vlahoviček, Kristian; Raimundo, Nuno; Kriško, Anita (2017) TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan. Aging Cell, 16 (5). pp. 994-1005. ISSN 1474-9718

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Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activityand consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases.

Item Type: Article
Additional Information: This work was supported by the Fondation Nelia et Amedeo Barletta, NAOS Group, and the Mediterranean Institute for Life Sciences to AV, MP, MM, MR, AN, and AK; Croatian Ministry of Science, Education and Sports, Grant No. 098-0982464-1647 to AS and SS; European Commission Seventh Framework Program, Integra-Life; grant 315997 to KV; FP7-REGPOT-2012-2013-1, Grant No. 316289, InnoMol to AMM; grant 337327 from the European Research Council to NR and PBD; IM is supported by an Emmy Noether Award from the Deutsche Forschungsgemeinschaft.
Uncontrolled Keywords: ageing; glucose starvation; mitochondria; protein chaperones; replicative lifespan; Snf1/AMPK; TORC1; yeast
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
Sustav citokroma P450 i pojava tumora u starenju i oksidacijskom stresu-Tihomir Balog098-0982464-1647MZOS
Enhancement of the Innovation Potential in SEE through new Molecular Solutions in Research and Development-INNOMOLUNSPECIFIED316289EK
European Research CouncilUNSPECIFIED337327UNSPECIFIED
Integrating research in molecular life sciences at the University of Zagreb-INTEGRA-LIFEUNSPECIFIED315997EK
Depositing User: Sandra Sobočanec
Date Deposited: 05 Apr 2018 08:58
DOI: 10.1111/acel.12623

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