Can you imagine being so hungry that you have to eat your own body parts? Sounds gruesome, doesn’t it? But guess what? We have all been doing it many times! How? It is through our cells. When living cells experience a severe shortage in nutrient supply, they often devour unnecessary and dysfunctional components to generate the amino acids and nutrients needed to produce energy and perform basic functions. This well-regulated self-eating process is called ‘autophagy’.
Studies have shown that autophagy not only helps cells survive periods of starvation, but also maintains cellular equilibrium — both of which are essential for the survival and normal functioning of cells. Hence, it becomes all the more important in cells with longer life span, like neurons. This process also plays an important role in immune response and controls inflammation and activation of adaptive immunity. It is no coincidence that defects in autophagy have been linked to neurodegenerative diseases like Parkinson’s disease.
Molecular mechanisms
“Autophagy keeps the cells and organisms healthy by removing damaged organelles and aggregated and misfolded proteins, fighting infections and preventing cancer. Defects in autophagy lead to several prevalent disorders including neurodegenerative diseases and hampered immune response. Because autophagy has direct relevance to human health and disease, it is necessary to understand the molecular mechanisms underlying it,” says Dr Ghansyam Swarup, a molecular biologist at the Centre for Cellular and Molecular Biology, Hyderabad. Alterations in autophagy are also observed in cells affected by cancer, metabolic dysfunction, vascular instability, cardiomyopathies, myopathies and non-alcoholic fatty liver diseases.
Today, autophagy is an important field of research. The fact that the 2016 Nobel Prize in Physiology was awarded to the Japanese cell biologist Dr Yoshinori
Ohsumi is a testimony to this. The interest in autophagy started with the discovery of lysosome, a cell organelle that contains enzymes that can break down all the
biomolecules, by Christian de Duve in 1955. Following that, many studies employed electron microscopy to observe lysosome and established that the degradation of foreign particles that takes place inside them. The vesicle, which carries
foreign bodies to lysosome, was termed phagosome.
More studies discovered similar membrane structures containing cellular organelles like mitochondria and other cytoplasmic constituents. These double membrane-bound structures, which could be induced by certain chemical treatments or stress conditions, were shown to fuse with lysosome. The term ‘autophagy’ was coined to refer to this mode of delivery of cytoplasmic materials to lysosome for degradation. The lack of sophisticated instruments and unavailability of biomarkers limited further studies during the 1970s and 1980s.
The real breakthrough came in 1993 when Dr Yoshinori and his colleagues isolated 15-autophagy deficient mutants in yeast. “This required development of a yeast strain deficient in three lysosomal enzymes, which accumulated non-degraded material in its lysosome when autophagy was induced and could be seen under a light microscope. Using this yeast strain, he could identify and isolate autophagy-defective mutants because they did not accumulate non-degraded material in the vacuole. Subsequent cloning of these genes led to identification of molecular markers for the study of autophagy in yeast,” explains Dr Ghansyam. “Since most of these autophagy genes are also present in mammalian cells, his work helped in exploring autophagy mechanisms even in mammalian cells,” he adds.
Autophagy is classified into three types: macroautophagy, microautophagy and chaperone-mediated autophagy. During earlier days of research, only macroautophagy was known. It is the most common type and begins with the appearance of a small membrane sac in the cytoplasm, which then extends into a double membrane-bound structure enclosing a portion of the cytoplasm. This double membrane-bound structure, called autophagosome, then fuses with lysosome, where the actual degradation and recycling takes place. In microautophagy, autophagosomes or similar structures are not involved and the lysosome engulfs the constituents to be degraded directly from the cytoplasm.
Researchers are trying to develop drugs that can either induce or inhibit autophagy, and studies are also being carried out to repurpose known drugs, which are reported to enhance or inhibit autophagy, for new clinical applications. But, to effectively use drug-induced inhibition or enhancement of autophagy as a therapeutic measure, we need to identify the steps affected in causing these diseases.
Dr Yoshinori’s identification of autophagy-related genes in yeast was a turning point in this direction. The hallmarks of this study are a design of elegant methodologies, which could be extended to higher animals and near-complete description of autophagy in a model organism like yeast.
Research trends
Despite the enormous volume of work over the past two to three decades, autophagy research is still in its early stages. “There are so many questions that remain to be answered about the unique membrane dynamics that constitute autophagy, and there are still many mysteries that need to be uncovered before we truly understand the molecular mechanisms of autophagy,” wrote Dr Yoshinori in a 2014 review.
Autophagy research is an active area in India too. “Several groups in India are actively working to understand molecular mechanisms of autophagy and their role in various diseases. They are using a variety of experimental models including cell culture and animal models, and pathogens such as malarial parasite and Leishmania donovani,” remarks Dr Ghansyam. The mutations in optineurin are reported to cause both glaucoma and Amyotrophic lateral sclerosis (ALS). Understanding connections between autophagy and human diseases, characterisation of genetics of autophagy in other organisms and the role of autophagy in immune responses are some of the themes being explored by various research groups across the globe. With further advancements in analytical techniques, we would hopefully be able to tap into the enormous potential of the self-snacking abilities of cells – ‘autophagy’.
(The author is with Gubbi Labs, a Bengaluru-based research collective)