Perturbations in L-serine metabolism regulate protein quality control through the sensor of the retrograde response pathway RTG2 in Saccharomyces cerevisiae

Cellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since most of these processes are energy-driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse and metabolic imbalance are both linked to aging and age-associated disorders, yet they have traditionally been studied as separate phenomena in the context of aging. In this study, we indicate that reduced proteostasis capacity is a result of a metabolic imbalance associated with age. We observed increased accumulation of L-serine and L-threonine in replicative old cells of Saccharomyces cerevisiae, indicating an imbalance in amino acid metabolism with replicative aging. Replicating this metabolic imbalance in young cells through deletion of serine-dependent transcriptional activator, CHA4, resulted in increased aggregation of endogenous proteins along with misfolding-prone proteins Guk1-7ts-GFP and Luciferase-GFP in both young and old cells. Aggregate formation in the cha4Δ strain required a functional sensor of mitochondrial dysfunction and an activator of the retrograde signaling gene, RTG2. CHA4 and RTG2 exhibited genetic interaction and together regulated mitochondrial metabolism, replicative lifespan, and aggregate formation in young cells, connecting metabolic regulation with proteostasis and aging. Constitutive activation of retrograde signaling through overexpression of RTG2 or deletion of MKS-1, a negative regulator of Rtg1-Rtg3 nuclear translocation, resulted in faster resolution of aggregates upon heat shock through RTG3 and was found to be independent of molecular chaperone upregulation.