mTOR signaling in autophagy regulation in the kidney

Abstract

Cells possess adaptive biosynthetic systems to maintain cellular energy levels for survival under adverse environmental conditions. Autophagy is an evolutionarily conserved cellular catabolic process that breaks down and recycles cytosolic material including macromolecules and organelles through lysosomal degradation. This catabolic process, represented by macroautophagy, is induced by a variety of cellular stresses such as nutrient starvation, which causes a shortage of cellular energy for cells to maintain cellular homeostasis and essential biological activities. In contrast, upon nutrient availability, cells stimulate anabolic processes. The mechanistic/mammalian target of rapamycin, a serine/threonine protein kinase, is a key player in stimulating cellular anabolism in response to nutrients and growth factors, and plays a crucial role in suppressing autophagy activity. Growing evidence has suggested that autophagy activity is required for the maintenance and physiological functions of renal cells including proximal tubular cells and podocytes. In this article, we discuss recent progress in the regulation of autophagy by mechanistic/mammalian target of rapamycin signaling.

Keywords: AMPK; Autophagy; mTOR; mTORC1; podocyte; rapamycin; renal proximal tubular cell.

Figure 1. Signal transduction in the regulation mTORC1 activation and autophagy inhibition

Two small GTPases, Rheb and Rags cooperatively stimulate mTORC1 on the lysosomal membrane in response to growth factor and amino acid, respectively. Active mTORC1 phosphorylates multiple components in the ULK1 (ATG1) complex and inhibits its function, whereas AMPK and ULK1 phosphorylation of the components in the complex stimulates its function to induce autophagy.