Maternal Nutrition and Placental Autophagy

Category: Biology
Date added
Pages:  7
Words:  1980
Order Original Essay

How it works


Autophagy is a highly conserved and regulated process that occurs in cells to maintain cellular homeostasis. It is a catalytic process in which cytoplasmic components, such as macromolecules, organelles, and debris, are degraded, thus providing new building block for cellular recycling. Autophagy is also important for promoting cell survival in response to stressful environmental cues. This stress response provides an alternate route for cells during nutrition deprivation, hypoxia, high endoplasmic reticulum (ER) stress, and many others. Nutrition deprivation, hypoxia, and high ER stress will be the focus of this review. Previous research articles have shown that autophagy is important for establishing pro-survival signals within a cell when it undergoes significant environmental stresses. This suggests that there is a delicate balance between adaptive autophagy and apoptosis during stress-inducing situations.

Various studies have explored the mechanisms by which autophagy occurs in many cell types and environments. These have resulted in identifying three main molecules that are essential for autophagy to occur, as well as being the key way to confirm the level at which autophagy is occurring. Beclin 1 (BECN1) regulates both autophagy and apoptosis through its importance in synthesis and growth of autophagosome membranes. Microtubule-associated protein 1 light chain 3 (LC3) integrates into the membrane of autophagosomes, which is important when the vesicle must fuse with the lysosome. Lastly, DRAM is a p53-induced modulator of autophagy which acts via the lysosome.

It has already been shown that autophagy is induced shortly after oocyte fertilization. Researchers also believe that autophagy occurs within the placenta during gestation, however, they are unsure of the levels at which autophagy occurs. Understanding the occurrence of placental autophagy will provide an insight to the maintenance mechanisms autophagy has for a successful pregnancy and embryo survival. More recently, researchers have begun to study the mechanism of autophagy within the placenta. This is such a new area of research in this topic due to the complex mechanisms involved as well as the difficulty of analysis. However, understanding exactly what is occurring during gestation in terms of autophagy of the placenta will provide researchers an insight into a vast number of diseases that can occur during pregnancy. This is not only important for the health of the mother, but also the long-term help of the child.

Thus far, research has been limited in this area and has focused more on the general mechanisms involved. This review will be focused on the specific connection between placental autophagy and maternal nutrition. Understanding the proteins and genes involved, as well as the pathways they act through, will help caretakers provide better nutritional information and overall care for mothers experiencing high-risk pregnancies. Mainly, this review will look at the negative effects nutritional deprivation has on placental autophagy and how it can lead to fetal growth restriction (FGR).

Autophagy Overview

Mechanisms of Autophagy

Many researchers have investigated the stepwise mechanism of autophagy. Knowing the general steps of this process will allow future researchers to discover the mechanisms by which autophagy occurs in more complex cells and tissues. As depicted in Figure 1, the process of autophagocytosis follows the same five steps independent of the cell or tissue type. Autophagy begins with the formation of a single isolation membrane, called a phagophore. This single membrane elongates to form a vesicle with a double membrane. Following the process of vesicle elongation, the isolation membrane invaginates and collects all manners of cellular debris. Vesicle maturation will result in an autophagosome. From here, the autophagosome moves to the lysosome and fuses with it. Lysosome enzymes are now able to digest the cellular cargo and degrade the vesicle membrane.

Having discovered the mechanism by which autophagy occurs, research could move into the induction mechanisms and the specific signaling pathways involved. Several stimuli have been discovered to induce autophagy, including starvation, nutritional status, ER stress, immune signals, mitochondrial damage, hypoxia, and redox stress. Both starvation and nutritional stress are the most well-known and thus have been studied in many model organisms. Correspondingly, researchers have uncovered several upstream signaling pathways that are intimately involved in stimulating autophagy. The two main pathways that have been discovered are the phosphatidylinositol 3-kinase (PI3K)/Akt and mTOR pathways. PI3K/Akt acts by negatively regulating Beclin 1, thus stimulating mTOR. Stimulation of mTOR will result in the inhibition of autophagy. mTOR activity regulates autophagy based on the nutritional status of the tissue. In nutrient replete conditions, mTOR activity blocks autophagy. However, during nutrient deprivation, mTOR activity becomes suppressed. mTOR suppression leads to the activation of UNC-51-like kinase 1, thus initiating autophagy within that cell. These signaling pathways will be discussed more thoroughly in the context of placental autophagy later in this review.

Regulation of Autophagy

Nutritional Status

Nutritional status, mainly nutritional deprivation, is an extremely well-known autophagy inducer. It is characterized by mTOR inhibition via two downstream transcription related signaling pathways. The first pathway acts through Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). When growth factors, such as insulin or insulin-like growth factors, bind to their corresponding receptors on a cell, it can stimulate downstream effector molecules. Akt and ERK1/2, once active, can phosphorylate two tuberous sclerosis complexes (TSC1/2). Active TSC1/2 can then go on to suppress mTOR, which stimulates autophagy initiation. The second pathway regulates autophagy through AMP-dependent protein kinase (AMPK). AMPK activation depends on both intracellular Ca2+ levels and upstream kinase activity. Once active, AMPK is able to sense the AMP:ATP ratio of the cell, therefore checking the available energy of the cell. If energy is depleted, AMPK will go on to inhibit mTOR activity, via phosphorylation of TSC2, and induction of autophagy.

ER Stress

Unfolded proteins can induce autophagy due to their importance in the ER stress pathway. There are several ER-associated proteins involved within this signaling pathway, with protein kinase R-like eIF2? kinase (PERK) as the initial stimulatory molecule. PERK can be activated in response to hypoxic cellular conditions. Once active, PERK can induce LC3 and autophagy related-5 (Atg5) gene transcription or it can induce activating transcription factor-4 (ATF4) via eIF2? phosphorylation. The last mechanism by which ER stress can activate autophagy is through inositol-requiring enzyme 1 (IRE1). This is a serine/threonine kinase which either stimulates autophagy by activating Jun N-terminal kinase 1 (JNK1) or inhibits autophagy via the X-box binding protein 1.


Autophagic induction in response to hypoxia can occur by one of two pathways depending on the level of hypoxia. Under moderate hypoxia conditions, hypoxia-inducible factor 1-? (HIF1-?) is predominant. This pathway acts through the transcription of Bcl-2, thereby weakening the interaction between Beclin 1 and Bcl-2. Without a strong interaction between these two molecules, autophagy is elicited. Also, HILF1-? phosphorylates TSC1/2 inhibiting mTOR activity and increasing autophagy. Severe hypoxic conditions induce autophagy via a HIF1-? independent response. This pathway activates AMPK thus inhibiting the mTOR activity. Severe hypoxia can also elicit an unfolded protein response.

Autophagy Assessment

Electron Microscopy

Electron microscopy is the most conventional form of microscopy to use when studying autophagy. However, there is one major drawback to this commonly used method; it is very difficult to distinguish between the single- and double-membrane autophagosomes. Because of this, the vesicles are lumped together when using this analysis technique. Quantification of autophagy by electron microscopy is achieved by calculating the ratio between the area of autophagic vesicles and the total cytoplasmic area. However, calculating this ratio is extremely difficult and thus requires highly skilled experts and extended periods of time. Additionally, even the highly skilled scientists can mistake other organelles as an autophagic vesicles. Because of this, quantification of autophagic markers has been much more popular as the science in this area progresses.

Immunofluorescence of Autophagic Markers

Immunofluorescence is a common technique used to follow the localization of molecules, proteins, and genes within a cell. For autophagy, localization of Beclin 1, LC3, and DRAM within a tissue would be enlightening. Tissue section staining, or real-time tissue staining is possible through this method by using antibodies specific for the antigen. The antibodies used can be either bond to GFP or a secondary antibody can be used to follow the localization of the molecules. Once staining is complete, confocal microscopy is required to view the fluorescence. Quantification of this method can be tricking, due to its basis on human observation.

Western Blot

Western blotting is one of the best methods by which to measure the relative level of autophagy. Most researchers perform western blots probing for LC3, since it is the considered the best molecule to asses autophagy in cells. Additionally, western blots are commonly probed for Beclin 1 and DRAM.

Autophagy and Apoptosis

There is a growing amount of evidence showing a connection between autophagy and apoptosis. Depending on the situation, this relationship can be either inhibitory or stimulatory. The following paragraphs will outline the several scenarios that have been previously proposed.

The first scenario suggests that autophagy often proceeds apoptosis. This allows autophagy to play a cytoprotective role by removing all proapoptotic stimuli. Without these apoptotic stimuli, the cell is able to survive in spite of stressful conditions. This scenario of autophagy sets a threshold for cellular escape from death and thus maintaining survival. Death escape only works up until a point at which the excessive toxic signals overwhelm the cell and apoptosis ensues.

The second scenario suggests that autophagy reduces apoptosis and vice versa. This cross-talk is largely inhibitory. During cellular apoptosis, selective autophagy can modify the apoptosis by increasing the cells threshold. This means that a reduction in autophagy increases the chance a cell will undergo apoptosis. On the other hand, apoptosis can inhibit autophagy within cells. This possibly occurs because apoptosis degrades certain proteins that are essential for autophagy to occur.

Lastly, the third scenario suggests that autophagy will lead to or induce apoptosis. This mechanism begins with autophagy responding to a primary stimulus. Eventually, the autophagic response will trigger apoptosis within the cell. Some researchers have connected this relationship to the expression and transcription of Beclin 1 and ATG genes.

Related Human Diseases

It is already known that autophagy plays an important role in the metabolism of carbohydrates, proteins, and lipids within the body. When these mechanisms go awry, diabetes, obesity, and atherosclerosis are a few of the diseases that can develop. Diabetes, particularly type 2 diabetes, has been the most studied disease in terms of autophagy. Researchers have shown that when autophagy becomes dysregulated within pancreatic ß-cells, patients develop insulin resistance. This correlates with the pathogenesis of type 2 diabetes. Several studies have shown an increase in formation of autophagosomes under these conditions. Additionally, pancreatic ß-cells are responsible for large amounts of protein folding. With such high depends, these cells tend to accumulate more misfolded proteins thus increasing the amount of ER stress within the cell. As discussed previously, increased ER stress is an inductor of autophagy.

Having discovered the various mechanisms in which autophagy is important within ß cells, researchers have concluded that similar methods are most likely present within the placenta. This belief stems from the knowledge that the placenta is responsible for an increasingly large amount of hormone biosynthesis throughout gestation. The additional work load could lead to increased protein misfolding, ER stress and thus autophagy. These hypotheses led researchers to drawing connections between placental autophagy and two high-risk pregnancy complications, fetal growth restriction (FGR) and fetal hypoxia. Researchers believe that increased autophagy in the placenta can inhibit fetal growth based on maternal nutritional status, thus resulting in FGR. On the other hand, fetuses that experience hypoxic conditions due to unhealthy mothers can result in the induction of autophagy in the placenta in order to prevent cell death. The particular roles autophagy plays in the placenta, especially in terms of these two conditions, needs further exploration.



  1. Oh, S.-Y., & Roh, C.-R. (2017). Autophagy in the placenta. Obstetrics & gynecology science, 60(3), 241-259.
  2. Tai-Ho, H., T’sang-T’ang, H., Szu-Fu, C., Meng-Jen, L., & Yi-Lin, Y. (2013). Autophagy in the Human Placenta throughout Gestation – ProQuest. PLoS One, 8(12).
Did you like this example?

Cite this page

Maternal Nutrition and Placental Autophagy. (2021, May 20). Retrieved from

The deadline is too short to read someone else's essay

Hire a verified expert to write you a 100% Plagiarism-Free paper