Autophagy is a cellular recycling mechanism by which cells consume themselves to maintain cellular energy and to protect tissues from cells that have suffered both external and endogenous damage.

In recent years, the autophagy process has been gaining increasing interest due to its fundamental role in maintaining homeostasis. In fact, in 2016 the Nobel Prize for Medicine and Physiology was awarded to Yoshinori Ohsumi for his discovery of autophagy in yeast and identifying the essential genes related to this process.

How does autophagy work?

There are 3 kinds of autophagy according to their mechanism:

  • Macroautophagy begins with the formation of intracellular vesicles, from part of the plasmatic membrane, which will include cellular organelles that are damaged. Subsequently, these vesicles, called autophagosomes, fuse with lysosomes that contain enzymes that degrade and eliminate the vesicular contents.
  • Microautophagy occurs directly in the lysosomes, called on this occasion autolysosomes, which are formed by the accumulation of membrane structures that invaginate directly into the lysosomes where they degrade.
  • Autophagy mediated by chaperones in which the proteins to be degraded are marked and subsequently recognized by the chaperones that transport them to the lysosomes where they are degraded.

The result of any of the three types of autophagy is the degradation into simpler molecules that are used for other metabolic processes. Thus, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cell renewal and homeostasis [1].

Autophagy can be induced by fasting and other ways of increasing stress on the body. During fasting, cells recover nutrients through autophagy to continue functioning. Specifically, the enzymes Ulk and Atg are actively involved in the cytoplasm-to-vacuole targeting pathway under nutrient-rich conditions, they switch to induce autophagy upon starvation by forming an autophagy-initiating complex with other kinases [2].

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In addition to the removal of impaired organelles and aggregated proteins, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability, and prevents necrosis, giving it a key role in disease prevention. [3]. All this makes autophagy a very interesting process in the maintenance of an organ as exposed as the skin. In fact, all three types of autophagy in the skin start with the same pathway, the inhibition of mTORC1 leading to the activation and formation of autophagosomes [4].

Autophagy in skin aging

As we saw in a previous post, skin aging is determined by different factors, both intrinsic and extrinsic. During this process the regeneration capacity of the skin decreases, it loses elasticity, thickness and pigmentation increases. Many of these aging processes are induced or increased by the presence of damaged molecules and organelles inside the cells, the elimination of these is partially regulated by autophagy [5]. So autophagy, by maintaining cellular homeostasis, allows reducing or slowing down aging processes.


The role of autophagy in keratinocytes was seen in a study in which autophagy in epidermal keratinocytes was suppressed, it was observed that it was not essential for the maintenance of the barrier function since the epidermis formed by these keratinocytes had a normal thickness and did not lose more transepidermal water [6].


Elimination of autophagy in melanocytes could decrease pigmentation changes in mature skin. In this sense, the elimination in melanocytes of the enzyme Atg7 involved in autophagy, resulted in age-dependent changes in skin pigmentation and development of premature senescence [7].


Thanks to autophagy in fibroblasts, the elimination of lipofuscin, an accumulation of misfolded modified proteins and lipids, is possible. The alteration of autophagy in senescent human fibroblasts could be related to the aberrant deposition of lipofuscin, which produces age-related pigmentation irregularities [8].

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Protection against UV damage

Ultraviolet radiation from the sun can cause damage to the skin that can become irreversible. UV rays produce DNA damage that induces a repair cascade and cell cycle interruption. During this break in the cycle, DNA recognition and repair occurs. However, if this damage is irreparable, it leads to programmed cell death, called apoptosis. Undamaged skin cells proliferate to replace those that have undergone apoptosis, but if the proliferation signalling process is interrupted, expansion of damaged cells can occur, inducing carcinogenesis.

One of the main signals is the p53 molecule, a key transcription factor in the activation of DNA damage repair. In addition, it induces the transcription of autophagy activators such as AMPK, TSC2, Sestrin 2 and Sestrin 2. UV B radiation rapidly induces autophagy through the activation of AMPK to regulate DNA damage repair, this activation of autophagy prevents the accumulation of UV-induced cellular oxidative damage by regulating UV-induced apoptosis, DNA damage repair, removal of oxidized lipids, and other responses to oxidative damage [9].

Role of autophagy in barrier function

The main function of the skin is to produce a semi-permeable protective layer. This layer is composed of different molecules in different layers. In this way, the outermost layer is known as the stratum corneum and protects against transepidermal water loss, as well as preventing foreign compounds from penetrating the dermis [10].

In addition to keratinocytes, the skin is composed of other cell types such as Langerhans cells, dendritic cells, melanocytes, and Merkel cells in the epidermis. Fibroblasts, endothelial cells, immune cells, and neurons in the dermis and adipocytes, nerves, and blood vessels in the hypodermis. Autophagy is necessary for the maintenance of the physiological activities of all these cells and the integrity of the skin, which helps maintain skin homeostasis and its barrier function [11].

Autophagy and skin diseases

Skin infections

Autophagy could help in processes of viral infections and other intracellular infections, as occurs in infectious dermatoses caused by the Epstein-Barr virus or by bacteria such as those of the genus Streptococcus and Mycobacterium, in which infectious particles are degraded [12].


Autophagy has also been identified in other skin diseases such as psoriasis. Thus, a genetic study has highlighted that a polymorphism of the Atg16L1 gene contributes to the risk of developing psoriasis. The protein encoded by the Atg16L1 gene is essential in autophagy processes since it regulates the excessive production of cytokines that results in chronic inflammation and tissue damage [13].


Finally, autophagy could also be involved in some cases of skin cancer such as melanoma. Melanomas are produced by the transformation of melanocytes into cancer cells. Dduring this process autophagy is reduced compared to healthy melanocytes [14]. However, once melanoma is established, autophagic activity increases again, allowing tumour cells to survive in a stressful microenvironment [15].


Autophagy plays a dual role in the skin; On the one hand, it is essential for maintaining its homeostasis, but on the other, its deficiency promotes cancer progression by increasing oxidative stress and the accumulation of DNA damage.

Thus, the treatment of autophagy could improve skin quality, but further research is still required to determine the role of autophagy in each skin process.


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  2. Shang, L., Chen, S., Du, F., Li, S., Zhao, L., & Wang, X. (2011). Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proceedings of the National Academy of Sciences of the United States of America, 108(12), 4788–4793.
  3. Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. The Journal of pathology, 221(1), 3–12.
  4. Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The Role of Autophagy in Skin Fibroblasts, Keratinocytes, Melanocytes, and Epidermal Stem Cells. The Journal of investigative dermatology, 140(9), 1691–1697.
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  7. Zhang, C. F., Gruber, F., Ni, C., Mildner, M., Koenig, U., Karner, S., Barresi, C., Rossiter, H., Narzt, M. S., Nagelreiter, I. M., Larue, L., Tobin, D. J., Eckhart, L., & Tschachler, E. (2015). Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes. The Journal of investigative dermatology, 135(5), 1348–1357.
  8. Ott, C., König, J., Höhn, A., Jung, T., & Grune, T. (2016). Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts. Redox biology, 10, 266–273.
  9. Sample, A., & He, Y. Y. (2017). Autophagy in UV Damage Response. Photochemistry and photobiology, 93(4), 943–955.
  10. van Smeden, J., & Bouwstra, J. A. (2016). Stratum Corneum Lipids: Their Role for the Skin Barrier Function in Healthy Subjects and Atopic Dermatitis Patients. Current problems in dermatology, 49, 8–26.
  11. Sil, P., Wong, S. W., & Martinez, J. (2018). More Than Skin Deep: Autophagy Is Vital for Skin Barrier Function. Frontiers in immunology, 9, 1376.
  12. Guo, Y., Zhang, X., Wu, T., Hu, X., Su, J., & Chen, X. (2019). Autophagy in Skin Diseases. Dermatology (Basel, Switzerland), 235(5), 380–389.
  13. Douroudis K, Kingo K, Traks T, Reimann E, Raud K, Rätsep R, et al. Polymorphisms in the ATG16L1 gene are associated with psoriasis vulgaris. Acta Derm Venereol. 2012 Jan; 92(1): 85–7.
  14. Liu H, He Z, von Rütte T, Yousefi S, Hunger RE, Simon HU. Down-regulation of autophagy- related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci Transl Med. 2013 Sep; 5(202): 202ra123.
  15. Hara Y, Nakamura M. Overexpression of autophagy-related beclin-1 in advanced malignant melanoma and its low expression in melanoma-in-situ. Eur J Dermatol. 2012 Jan-Feb; 22(1): 128–9.

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