mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival

Abstract

The mechanistic (or mammalian) target of rapamycin (mTOR) and the adenosine monophosphate-activated protein kinase (AMPK) regulate cell survival and metabolism in response to diverse stimuli such as variations in amino acid content, changes in cellular bioenergetics, oxygen levels, neurotrophic factors and xenobiotics. This Opinion paper aims to discuss the current state of knowledge regarding how mTOR and AMPK regulate the metabolism and survival of brain cells and the close interrelationship between both signaling cascades. It is now clear that both mTOR and AMPK pathways regulate cellular homeostasis at multiple levels. Studies so far demonstrate that dysregulation in these two pathways is associated with neuronal injury, degeneration and neurotoxicity, but the mechanisms involved remain unclear. Most of the work so far has been focused on their antagonistic regulation of autophagy, but recent findings highlight that changes in protein synthesis, metabolism and mitochondrial function are likely to play a role in the regulatory effects of both mTOR and AMPK on neuronal health. Understanding the role and relationship between these two master regulators of cell metabolism is crucial for future therapeutic approaches to counteract alterations in cell metabolism and survival in brain injury and disease.

Keywords: adenosine monophosphate-activated protein kinase; autophagy; cell death; energy failure; glycolysis; mammalian target of rapamycin; mitochondria; nutrient deprivation.

Figure 1. mTOR/AMPK signaling crosstalk

Signaling by mTOR and AMPK integrates changes in the cellular environment linked to growth factors, nutrient, oxygen and energy availability, excitotoxicity (Ca²⁺) and stress (oxidative stress). Five major points of convergence include: 1) the transcriptional regulation of genes linked to cell survival/death, proteostasis, redox balance and bioenergetics; 2) metabolism (central carbon and bioenergetics); 3) autophagy; 4) mRNA translation and protein synthesis; and 5) cell survival and growth (AKT). Arrows indicate activation. Stop lines indicate inhibition. Phosphorylation events (P) are color coded according to the kinase involved in phosphorylating the corresponding targeted protein. White background/colored “P” highlights an inhibitory effect; Colored background/white P highlights an stimulatory (activation) effect. A detailed explanation of the phosphorylation events is included in the Supplementary Table 1. Additional crosstalk might involve indirect pathways not highlighted in this figure.