Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast.
Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing of secretory proteins. By using the model organism Saccharomyces cerevisiae we show that calcium shortage leads to a slowdown of cell growth and metabolism. Accumulation of unfolded proteins within the calcium-depleted lumen of the endoplasmic reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections linking disturbance of ER calcium equilibrium to ER stress and UPR signaling are evolutionary conserved and highlight the crucial role of metabolism in modulating the effects induced by calcium shortage.
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO, Centre of Systems Biology, Milan, Italy.
Stefano
S
Busti
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|Department of Biology and Biological Engineering, Division of Industrial Biotechnology, Chalmers University of Technology, Gothenburg, Sweden.
Valeria
V
Mapelli
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO, Centre of Systems Biology, Milan, Italy.
Farida
F
Tripodi
Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.
Rossella
R
Sanvito
Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.
Fulvio
F
Magni
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO, Centre of Systems Biology, Milan, Italy.
Paola
P
Coccetti
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Marcella
M
Rocchetti
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
Jens
J
Nielsen
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO, Centre of Systems Biology, Milan, Italy.
Lilia
L
Alberghina
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|SYSBIO, Centre of Systems Biology, Milan, Italy.
Marco
M
Vanoni
D002118:Calcium / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D005285:Fermentation; D006706:Homeostasis; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism*; D056811:Unfolded Protein Response
D002244:Carbon; D002118:Calcium