The term ‘autophagy’, derived from the Greek meaning ‘eating of self’, was first coined by Christian de Duve over 40 years ago, and was largely based on the observed degradation of mitochondria and other intra-cellular structures within lysosomes of rat liver perfused with the pancreatic hormone, glucagon [1]. The mechanism of glucagon-induced autophagy in the liver is still not fully understood at the molecular level, other than that it requires cyclic AMP induced activation of protein kinase-A and is highly tissue-specific [2]. In recent years the scientific world has ‘rediscovered’ autophagy, with major contributions to our molecular understanding and appreciation of the physiological significance of this process coming from numerous laboratories [3–6]. Although the importance of autophagy is well recognized in mammalian systems, many of the mechanistic breakthroughs in delineating how autophagy is regulated and executed at the molecular level have been made in yeast (Saccharomyces cerevisiae) [3,7]. Currently, 32 different autophagy-related genes (Atg) have been identified by genetic screening in yeast and, significantly, many of these genes are conserved in slime mould, plants, worms, flies and mammals, emphasizing the importance of the autophagic process in responses to starvation across phylogeny [3].
There are three defined types of autophagy: macro-autophagy, micro-autophagy, and chaperone-mediated autophagy, all of which promote proteolytic degradation of cytosolic components at the lysosome. Macro-autophagy delivers cytoplasmic cargo to the lysosome through the intermediary of a double membrane-bound vesicle, referred to as an autophagosome, that fuses with the lysosome to form an autolysosome. In micro-autophagy, by contrast, cytosolic components are directly taken up by the lysosome itself through invagination of the lysosomal membrane. Both macro-and micro-autophagy are able to engulf large structures through both selective and non-selective mechanisms. In chaperone-mediated autophagy (CMA), targeted proteins are translocated across the lysosomal membrane in a complex with chaperone proteins (such as Hsc-70) that are recognized by the lysosomal membrane receptor lysosomal-associated membrane protein 2A (LAMP-2A), resulting in their unfolding and degradation [8]. Due to recent and increased interest specifically in macroautophagy and its role in disease, this review focuses on molecular and cellular aspects of macro-autophagy (henceforth referred to as ‘autophagy’) and how it is regulated under both healthy and pathological conditions