Autophagy and disease: always two sides to a problem

Abstract

Autophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular components in lysosomes. In recent years, intensive scrutiny at the molecular level to which autophagy has been subjected has also contributed to expanding our understanding of the physiological role of this pathway. Added to the well-characterized role in quality control, autophagy has proved to be important in the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodelling, and cellular defence against extracellular insults and pathogens. It is not a surprise that, in light of this growing number of physiological functions, connections between autophagic malfunction and human pathologies have also been strengthened. In this review, we focus on several pathological conditions associated with primary or secondary defects in autophagy and comment on a recurring theme for many of them, ie the fact that autophagy can often exert both beneficial and aggravating effects on the progression of disease. Elucidating the factors that determine the switch between these dual functions of autophagy in disease has become a priority when considering the potential therapeutic implications of the pharmacological modulation of autophagy in many of these pathological conditions.

Figure 1. Autophagic pathways

Three different general mechanisms of lysosomal delivery of cargo set the basis for the different types of autophagy described in mammalian cells (clockwise). A. Macroautophagy: Different extracellular and intracellular signals activate the recruitment of the macroautophagy initiation complex to the sites of autophagosome formation. Shuttling of proteins and lipids to these regions and posttranslational modifications of the lipids initiate the formation of a limiting membrane that grows through the assembly of proteins conjugated to proteins or lipids while it sequesters components of the cytosol. Once the membrane seals to form the autophagosome, this double membrane vesicle is delivered to lysosomes where upon membrane fusion, lysosomal hydrolases gain access to cargo. B. Microautophagy: Through stimuli yet poorly identified, cytosolic soluble proteins and organelles are directly sequestered by invaginations in the surface of lysosomes and late endosomes. Cargo internalized in the small luminal vesicles is degraded after the vesicles pinch-off from the limiting membrane. Although most microautophagy probably occurs in bulk, selective targeting by hsc70 of cytosolic proteins to forming microvesicles has been described. C. Chaperone-mediated autophagy: It is induced by stimuli such as prolonged starvation, oxidative stress and other conditions resulting in protein damage, but the signaling mechanism activated by these stimuli remain unknown. When CMA is activated, selective cytosolic proteins bearing a targeting motif are recruited by hsc70 and co-chaperones to the surface of lysosomes. Upon binding to the receptor protein LAMP-2A, substrates cross the membrane through the LAMP-2A-dependent translocation complex and are then rapidly degraded in the lumen.

Figure 2. Autophagy and Cancer

Autophagy may play opposite roles in the oncogenic process. Anti-tumoral effect (left): Active maintenance of cellular quality control for cytosolic pro-oncogenic proteins such as p62 prevents malignant transformation of non-tumoral cells. In addition, the supply of energy provided through macroautophagy activation, reduces the dependence on glycolysis while assuring the energy required for maintenance of a stable genome, further preventing oncogenesis. Pro-oncogenic effect (right): The reduction in macroautophagic activity in early stages of the oncogenic process favors malignant transformation as the accumulation of molecules such as p62 activates signaling mechanisms that promote necrosis and inflammation. Poor quality control as a result of diminished macroautophagy can also result in accumulation of defective mitochondria with the subsequent release of harmful molecules (cytochrome C and reactive oxygen species) that contribute to further alter genome maintenance. However, as the tumor progresses, activation of macroautophagy is observed in many oncogenic process in part to compensate for the poor nutritional supply associated to rapidly growing tumors and defend cancer cells against damage induced by anti-oncogenic therapies. In addition., enhanced mitochondrial degradation in this stage may contribute to the upregulation of glycolysis to maintain the energetic balance (Warburg effect) characteristic of malignant cells.

Figure 3. Autophagy and Neurodegeneration

A. Protective autophagy: Macroautohagy Macroautophagy and CMA both contribute to maintenance of neuronal homeostasis and are necessary in the defense of neurons against injury and stressors. B. Defective macroautophagy: Defects in macroautophagy have been described to occur at very different levels in neurodegenerative diseases. Some of the possible steps affected in this process are highlighted in the model and the conditions in which they have been observed are described in the text. C. Defective CMA: Primary defects in CMA have been described both in Parkinson’s disease and in certain tauopathies. While in the former condition, pathogenic proteins such as α-synuclein can block access of other cytosolic proteins to lysosomes via CMA by abnormally binding to the translocation machinery, in tauopathies the accumulation at the surface of lysosomes of oligomeric forms of pathogenic tau targeted via CMA destabilizes the lysosomal membrane and results in leakage of lysosomal enzymes in the cytosol which often triggers cellular death.

Figure 4. Autophagy and the immune system

A. Macroautophagy against pathogens: Macroautophagy contributes to the elimination of different types of pathogens – bacteria and viruses – when they escape to the cytosol after internalization in the phagosome. In certain conditions fusion of autophagosomes with phagosomes is required before degradation can occur. B. Pathogens using macroautophagy: Growing evidence supports that certain pathogens have evolved to utilize autophagosomes as a site of replication and can actively prevent the fusion of this compartment with lysosomes to guarantee their survival. C. Antigen presentation: All three forms of autophagy, macroautophagy, CMA and microautophagy have been shown to contribute to antigen loading of MCH class II molecules for presentation of antigens to activate T cells.