The importance and practical application of autophagy in human health

Introduction When we consider the important roles various parts of our cells have, it is often the classic organelles that come to mind—nuclei and DNA storage, mitochondria and energy production, endoplasmic reticulum and molecular transport, and the various others. Our recognition of their importance is not misplaced in the least, for without these structures our cells would cease to function. However, research over the past few decades, facilitated by advancements in technology and techniques, have uncovered other equally important cellular structures on which the cell relies upon for its maintained health and function. One such structure is the autophagosome, a small vesicle-like structure that engulfs damaged organelles and other cytoplasmic material for the transport to the lysosome for digestion. A large amount of today’s research on autophagy is pioneered by Noboru Mizushima, a nominee for the 2015 Nobel Prize in Medicine or Physiology. Mizushima was first intrigued by autophagy when he read an article about newly identified autophagy genes with unique amino-acid sequences (“Autophagy: Noboru Mizushima Interview Special Topic of Autophagy,” 2009). Inspired, he joined Dr. Yoshinori Ohsumi, the author of the article, in researching the molecular mechanism and physiological role of autophagy in yeast and mammals. Once there, Mizushima began to explore the physiological roles of autophagy. At its most basal level, autophagy is a mechanism by which other organic material is recycled. However, this design is modified in different cases to suit various functions. Mizushima categorizes autophagy into groups (microautophagy, macroautophagy, and chaperone-mediated autophagy) that each have specialized methods for delivering certain molecules to the lysosome (Mizushima, Levine, Cuervo, & Klionsky, 2008). These specialized autosomes can be distributed to various parts of the body depending on their function. For example, autophagy in the liver is stimulated by amino acids and autophagy in the muscles is instead stimulated by insulin (Naito, Kuma, & Mizushima, 2013). The importance of autophagy lies in its various roles. Autosome activity is governed by a multitude of genes that are specific to certain parts of the body. The basal regulators in this process are the autophagy-related (ATG) genes, which determine how selective autosomes are and the amount of activity expressed at any point in time (Mizushima et al., 2008). Mizushima explains that given the destructive potential of autophagy, regulation of this process is necessary in order to prevent damage. In one of his experiments, Mizushima found that autophagy is stimulated during starvation, leading to the breakdown of organic molecules into their constituent amino acids (Sahani, Itakura, & Mizushima, 2014). The SQSTM1 gene is upregulated by the availability of these amino acids, and SQSTM1 protein, which has an inhibitory effect on autophagy, is synthesized. While starvation induces autophagy, the autophagy pathway itself produces a negative-feedback loop in what is suggested to be a self-regulatory process to avoid excess selfdigestion. Autophagy is necessary for the proper cellular function, and knowledge of its physiological roles can be applicable to medical research. One of the potential applications for autophagy that Mizushima suggests is its use against tumor cells in cancer patients. He states that an ATG gene knockout can upregulate autophagy and stimulate apoptosis (Mizushima et al., 2008). Autophagosomes that target tumor cells could theoretically be stimulated through such a gene knockout, and a natural autoimmune response would destroy the tumorous cells. In another study by Mizushima, it was discovered that static encephalopathy was linked with autophagy suppression (Saitsu et al., 2013). Patients with encephalopathy expressed a mutation in the autophagy gene WDR45, which resulted in defective production of autophagosomes. Some neurodegenerative diseases are caused by the build-up of ubiquitin plaques in the brain (i.e. Alzheimer’s disease), which might normally be prevented through autophagy recycling. A treatment restoring autophagy might be effective in reversing neurodegeneration, though the means for accomplishing this would have to be investigated.