Autophagy fights disease through cellular self-digestion

Abstract

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.At first glance, it may seem perplexing that a process of cellular self-eating could be beneficial. In its simplest form, however, autophagy probably represents a single cell's adaptation to starvation-if there is no food available in the surroundings, a cell is forced to break down part of its own reserves to stay alive until the situation improves. In single-cell organisms such as yeasts, this starvation response is one of the primary functions of autophagy, but in fact this role extends up through to humans. For example, even on a day-to-day basis, autophagy is activated between meals in organs such as the liver to maintain its metabolic functions, supplying amino acids and energy through catabolism 1,2 .There are various types of autophagy, including micro-and macroautophagy, as well as chaperone-mediated autophagy (CMA), and they differ in their mechanisms and functions ( Fig. 1) 3,4 . Both micro-and macroautophagy have the capacity to engulf large structures through both selective and non-selective mechanisms, whereas CMA degrades only soluble proteins, albeit in a selective manner. The capacity for large-scale degradation is important in autophagic function, but it carries a certain risk, because unregulated degradation of the cytoplasm is likely to be lethal. On the other hand, basal levels of autophagy are important for maintaining normal cellular homeostasis. Thus, it is important that autophagy be tightly regulated (Fig. 2) so that it is induced when needed, but otherwise maintained at a basal level. Although a complete picture of autophagy regulation is not available, many aspects have been covered in recent reviews 5-8 .Both the non-selective and selective nature of autophagy, as well as basal and induced levels, are important in regard to the role of this process in human health and disease. Perhaps the most fundamental point is that either too little or too much autophagy can be deleterious, a Autophagy in cell survival and cell deathThe pro-survival function of autophagy has been demonstrated at the cellular and organismal level in different contexts, including during nutrient and growth factor deprivation, endoplasmic reticulum stress, development, microbial infection, and diseases characterized by the accumulation of protein aggregates 8-11 . This pro-survival function is generally believed to be adaptive, but, in the context of cancer, is potentially maladaptive 12 . Metabolic stress is a common feature of the tumour microenvironment and m...

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