Build-UPS and break-downs: metabolism impacts on proteostasis and aging

Abstract

Perturbation of metabolism elicits cellular stress which profoundly modulates the cellular proteome and thus protein homeostasis (proteostasis). Consequently, changes in the cellular proteome due to metabolic shift require adaptive mechanisms by molecular protein quality control. The mechanisms vitally controlling proteostasis embrace the entire life cycle of a protein involving translational control at the ribosome, chaperone-assisted native folding, and subcellular sorting as well as proteolysis by the proteasome or autophagy. While metabolic imbalance and proteostasis decline have been recognized as hallmarks of aging and age-associated diseases, both processes are largely considered independently. Here, we delineate how proteome stability is governed by insulin/IGF1 signaling (IIS), mechanistic target of Rapamycin (TOR), 5' adenosine monophosphate-activated protein kinase (AMPK), and NAD-dependent deacetylases (Sir2-like proteins known as sirtuins). This comprehensive overview is emphasizing the regulatory interconnection between central metabolic pathways and proteostasis, indicating the relevance of shared signaling nodes as targets for future therapeutic interventions.

Fig. 1. Proteostasis pathways.

Schematic overview of cellular proteostasis pathways. Protein (orange) synthesis at the ribosome (blue) is controlled at multiple level through regulated translation initiation or elongation. Already during translation molecular chaperones facilitate native protein folding and compartment-specific sorting (purple). Cytosolic and compartment-specific chaperones play a crucial role in protein quality control by supporting functional folding or prevention of protein aggregation (purple). In addition, dedicated molecular chaperones also facilitate protein ubiquitylation and proteasomal targeting or promote aggregate formation and autophagic disposal (dashed purple arrow). In case proteins are terminally misfolded or not used, proteolysis by the proteasome and autophagosome catalyze turnover (red). Noteworthy, both proteasomal and autophagosomal protein degradation are triggered by substrate ubiquitylation. Dedicated stress-response pathways coordinate proteostasis mechanisms (gray). Proteotoxic stress results in activation of specific transcription factors (TF) that bind to distinct regulatory elements (RE) in the DNA and mediate stress-compensatory responses to restore proteostasis. See text for details.

Fig. 2. Metabolic regulation of proteostasis pathways.

Schematic overview of central metabolic pathways. Arrowheads indicate the abundance of stimuli/metabolites activating respective signaling pathways (▲ upwards, high abundance/▼ downwards, low abundance). The effect of active signaling on proteostasis pathways is shown on the level of protein synthesis (blue), proteasomal and autophagosomal degradation (red), and responsiveness of stress-compensatory pathways (gray). The effect of pathway activation on the metabolic profile is indicated for anabolism (growth, proliferation) and catabolism (biomolecules, metabolites), respectively. The availability of cellular energy under physiological pathway activation is shown as loaded or empty battery icon, respectively. See text for details.

Fig. 3. Orchestration of metabolic pathways.

A schematic depiction of the interconnection between key metabolic pathways and pharmacological interventions. IIS and TOR signaling are activated upon energy availability and are connected via the serine/threonine kinase AKT. IIS promotes AKT activation in a PI3K- and PDK1-dependent manner. AKT in turn phosphorylates FOXO transcription factors and thereby prevents nuclear translocation. AKT and AMPK act antagonistically to regulate TOR signaling through inhibitory and activating phosphorylation of TSC2, respectively. AMPK and sirtuin activity are both induced by low-energy conditions. AMPK can possibly stimulate sirtuins by elevating the production the NAD⁺ biosynthetic enzyme Nampt, which increases the NAD⁺/NADH ratio. Vice versa, sitruins might deacetylate LKB1, which targets the AMPK-related kinase MARK1 ultimately enhancing AMPK phosphorylation. Sirtuin and AMPK signaling also promote FOXO-mediated transcriptional activity, either by direct deacetylation (−Ac) or by the phosphorylation-dependent activation of histone deacetylases (HDACs), respectively. Moreover, AMPK can block IIS by induction of the PIP₃ phosphatase PTEN. Several pharmacological interventions are available that reduce (▼) or stimulate (▲) the activity of the different metabolic pathways and are in part used to treat metabolic disorders in human patients. See text for details.

Fig. 4. Organ-specific physiological regulation of metabolism.

Overview on metabolic pathways and how they influence the metabolic profile of different tissues including, liver, adipose tissue, muscle, and brain. IIS and TOR signaling are activated upon nutrient deprivation and either trigger anabolic nutrient utilization or counteract catabolic processes that increase nutrient availability and lower appetite and feeding behavior. In contrast, AMPK signaling and sirtuins act in response to nutrient deprivation promoting nutrient replenishment but inhibiting nutrient/energy storage. Sirtuins promote feeding behavior and growth hormone (GH, somatotropin) as well as thyroid-stimulating hormone (TSH) secretion, which antagonize the action of insulin and increase fat breakdown to provide the energy necessary for tissue growth. Arrows indicate inhibition (▼) or stimulation (▲) of the metabolic processes.