Autophagy as a Survival Mechanism or a Cause of Disease

Abstract

Proper turnover of cellular components is crucial for all cells. If damaged or excessive content in the cell is not removed at a sufficient pace, normal cell functions may be compromised. The same may occur if the degradation of cellular components occurs at a rate that cannot be balanced by anabolic pathways. Autophagy is a major catabolic process that orchestrates the degradation of cytosolic components ranging from proteins and lipids, to organelles such as mitochondria. If correctly regulated, autophagy contributes to maintain proper homeostasis. Under certain circumstances, the autophagy flux does not match the cellular need, leading to either too much or too little autophagy. Here we have studied three different disease states where the speed of autophagy may be improper; cancer cachexia, age-related macular degeneration (AMD) and cancer. Patients that suffer from cachexia lose substantial amounts of body mass, particularly skeletal muscle. The condition is associated with reduced life quality and limited survival. Currently, there are no available treatments to cure cachexia. The development of therapeutic strategies is limited by a gap in our knowledge of the underlying mechanisms that cause the condition. The development of cachexia is linked to a metabolic imbalance tipped in the favor of catabolic decay. The individual contribution of autophagy in the development of the condition has not been firmly determined, but the process is believed to be increased in tissues of cachectic patients. We find that autophagy-accelerating bioactivity is present in sera from cancer patients that lose weight and we identify IL-6 as an autophagy-accelerating signaling molecule that may contribute to cachexia. Furthermore, we unravel underlying mechanisms that occur in the tumor or tumor microenvironment that causes elevated level of IL-6. AMD is a neurodegenerative disease of the eye and the leading cause of blindness in the western world. AMD is characterized by the accumulation of protein and lipid deposits (drusen and lipofuscin). Accumulation of such deposits is associated with insufficient autophagy. We find that by increasing autophagy using the n-3 PUFA DHA, we can make cells more resistant to stress situations that are associated with formation of cellular deposits and therefore disease development. This suggests that autophagy acceleration may be preventive against diseases that are characterized by accumulation of harmful cellular deposits and aggregates. The regulation of autophagy in cancer cells have been a subject of much controversies. Generally it is believed that autophagy will protect cells from conditions that may otherwise increase mutation rates and contribute to carcinogenesis. In this regard, autophagy should be downregulated for tumors to develop. On the other hand, once tumors have established, they may depend on autophagy in order to survive. It is however, uncertain how and if autophagy may be accelerated again post-tumor establishment. We find that the basal autophagy flux in a cancer cell is a determinant as to whether the growth of cancer cells is affected by DHA. DHA can increase the level of reactive oxygen species and other stress situations that may normally be encountered by autophagy. In cancer cells with low basal autophagy, DHA compromises cell growth. This urges the development of good methods that enable us to determine in vivo autophagy flux, as that can help us identify tumors that could be growth inhibited by DHA. This study emphasizes the importance of a correctly tuned autophagy regulation, as either too much or too little autophagy may cause disease. Additionally, if we can determine the autophagy flux during different disease states, we may be able to target this process in order to treat or prevent disease.