Physiological role of autophagy as an intracellular recycling system: With an emphasis on nutrient metabolism

Abstract

Autophagy is a major intracellular degradation system in which the cytoplasmic contents are degraded in the lysosome. Its fundamental and evolutionarily conserved role is adaptation to starvation. Recent studies using autophagy-defective mutants of various organisms including mammals have indeed demonstrated the importance of autophagy during starvation; however, the exact mechanism underlying this beneficial effect remains unclear. In addition, it is now apparent that autophagy is also important for cellular homeostasis even under non-starvation conditions, and both non-selective and selective types of autophagy appear to be critical for this function. Here, we discuss the role of this catabolic pathway in recycling intracellular components, with particular reference to nutrient metabolism.

Introduction

Macroautophagy (referred to as autophagy hereafter) is an evolutionarily conserved catabolic process, whereby cytoplasmic components are sequestered in a double-membraned vesicle, termed an autophagosome, and delivered to the lysosome for degradation [1], [2], [3], [4], [5], [6]. Upon fusion with the autophagosome outer membrane, the lysosome provides the autophagosome with various types of hydrolytic enzymes, including proteases, lipases, glycosidases, and nucleases. Therefore, autophagy is simultaneously able to degrade various types of cytoplasmic components. Indeed, electron microscopy evidence shows that autophagosomes contain not only cytosol, but also intracellular structures such as the endoplasmic reticulum (ER), mitochondria, lipid granules, and glycogen granules, as well as membrane structures [7]. This “bulk degradation” may be the most characteristic feature of autophagy. After degradation, the resultant molecules are recycled to the cytosol. As autophagy is considered to be a non-selective and random degradation system, cytosolic proteins and RNA may be the primary substrates as they are present in relatively large amounts. Although there have been some studies of autophagic degradation of RNA in rat liver [8], [9], the role of autophagy has been investigated mainly by focusing on protein degradation.

The metabolic roles of autophagy can be classified into two types: basal and induced autophagy [10]. In nutrient-rich conditions, autophagy is suppressed but still occurs at low levels constitutively (basal autophagy). The role of basal autophagy is intracellular quality control through constitutive turnover of cytopolasmic components. When cells are subjected to starvation, autophagy is induced immediately (induced autophagy). Induced autophagy maintains the amino acid pool inside cells to adapt to starvation. Indeed, the level of amino acids in autophagy-deficient yeast cells is lower than that in wild-type cells during starvation [11]. Likewise, the amino acid levels in autophagy-deficient mice are 30–40% lower than in wild-type mice at 10 h after birth (neonatal starvation period), even though the levels are normal at birth [12], [13], [14]. Although providing amino acids to cells through autophagic degradation is important for adaptation to starvation, it remains unclear how the resultant amino acids are used. There are three possible ways to use amino acids: (i) new protein synthesis, (ii) energy production, and (iii) gluconeogenesis (Fig. 1). This issue needs to be addressed in order to understand the role of autophagy in protein metabolism. Recent genetic studies in mice have demonstrated the close association between autophagy and nutrient metabolism. In this review, we focus on the role of autophagy in macromolecule metabolism and intracellular homeostasis.