Autophagy: More than just in-house cleaning

The term ‘autophagy’ is derived from the Greek meaning ‘eating of self’ and was first coined by Nobel Prize-winning Belgian cell biologist Christian de Duve almost half a century ago1. Just a week ago, Yoshinori Ohsumi received the Nobel Prize in Physiology or Medicine for discovering the mechanistic details of autophagy2.

Yoshinori Ohsumi, Nobel Prize Winner, 2016
For a long period since the discovery of autophagy (1955), our understanding of the molecular underpinnings of this fundamental pathway of degradation was lacking, and autophagy was basically considered the ‘garbage-disposal system of the cell’ - a bulk, non-specific degradation of cellular junk3.

Image from Biocomicals
Contrary to the above notion, it has now been demonstrated that autophagy is highly specific and carefully orchestrated to meet the energy requirements of the cell. Further, autophagy enables the cell to cope with its dynamic microenvironment4. Dr. Ohsumi identified most of the key proteins and diverse pathways involved in the process, showed how the cells sense metabolic states, and collaboratively outlined the fine mechanistic details of autophagosome formation in yeast5. Ohsumi’s work continues to provide the basis for our present understanding of autophagy pathway.
Autophagy is critical for generating the energy required for cellular development and differentiation in response to metabolic stress. At the same time, autophagy also has a key role in housekeeping by removing misfolded or aggregated proteins, and recycling senescent organelles, like mitochondria, endoplasmic reticulum, and peroxisomes. Also importantly, autophagy plays an essential role in eliminating intracellular pathogens and helps in preventing and combating diseases. Therefore, autophagy is considered a process vital for survival6.
Morphologically, the proteins involved in core autophagy machinery are highly conserved from yeast to mammals. Autophagy is classified into three different types.
  1. Macroautophagy: The main pathway of autophagy in which cellular contents (damaged organelles, cytosolic proteins, and invasive microbes) are degraded by lysosomes or vacuoles are recycled. This is achieved by formation of double walled vesicle called an autophagosome. This autophagosome encloses cellular material and then fuses with the lysosomes and forms an autolysosome. Organelle-specific macroautophagy includes mitophagy, pexophagy, and ribophagy, etc.
  2. Microautophagy: The pathway where the lysosome directly takes action by engulfing the cytosolic material (or cargo), which involves direct invagination or protrusion/septation of the lysosomal/vacuolar membrane.
  3. Chaperone-mediated autophagy: Mechanistically, it is unrelated to the other two types of autophagy, and only occurs in mammalian cells. In this pathway, the cytosolic molecular assistants or chaperones (like heat shock protein, hsc-70) act as mediators and bring the targets into the lysosome.

Image adapted from Journal of cell Science
Autophagy is not simply a non-selective bulk degradation pathway for degradation of intracellular components. It has been clearly shown that both micro and macroautophagy can be selective or non-selective7. Although the mechanisms regulating all aspects of both selective and non-selective autophagy are not completely understood in humans, most aspects have been well characterized in a yeast model system.

Adapted from Cell Res 2014
The last decade has remarkably improved our understanding of autophagy, not only in terms of the molecular mechanisms that control it, but also with the broad physiological roles of autophagy in health and disease8. Many observations demonstrate strong links between autophagy and human diseases. It has been shown that tumor suppressor genes stimulate autophagy, whereas oncogenes inhibit autophagy. These are supported by the mechanistic overlaps between the pathways involved in regulation of autophagy and tumorigenesis9. Autophagy is also crucial for neuronal homeostasis, predominantly by preventing accumulation of protein aggregates, which affect the function of neurons. Studies in mice showed that mice lacking Atg5 or Atg7 display severe neurodegeneration in the central nervous system. A recent study also showed that recessive mutations in a key factor (EPG5), required for the maturation of autolysosomes, play a causative role in Vici syndrome which is characterized by cataracts, hypopigmentation, cardiomyopathy, psychomotor retardation, and immunodeficiency9.
Although there is remarkable improvement in our understanding of autophagy, there are still many basic questions that are unanswered. For instance, what decides which of the two pathways (macro or microautophagy) is responsible for degradation of a specific compound or organelle? And how does the autophagy machinery recognize that certain components are to be degraded? How are certain components protected against degradation? Hopefully in the near future we will have answers for these questions as well.
Do you do research on autophagy? Do you think the autophagic pathway can be a target for treatment of various disease? Let us know at!
View our autophagy reagents.

  1. Autophagy Wikipedia
  2. Yoshinori Ohsumi Nobel prize press release
  3. Medicine Nobel for research on how cells ‘eat themselves’
  4. Historical landmarks of autophagy research
  5. Autophagy: close contact keeps out the uninvited
  6. Autophagy: principles and significance in health and disease
  7. Autophagic processes in yeast: mechanism, machinery and regulation
  8. Autophagy in infection, inflammation and immunity
  9. Autophagy and human diseases
Contributed by Nidhi Vashistha, PhD.
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