Glyoxalase - skin’s inner defense system - limits protein damage in cells and tissues
Interview with Carine Nizard, Dior Science researcher, and Isabelle Petropoulos, associate professor at the Université Pierre and Marie Curie (UPMC-Sorbonne Université).
The collaboration between UPMC and Dior Science began 18 years ago and was instigated by UPMC laboratory director Bertrand Friguet and research scientist Carine Nizard of LVMH laboratories. We talk to Carine Nizard and long-time colleague Isabelle Petropoulos of the UPMC about the group’s work.
Bel Dumé: Could you explain the background to your work?
Carine Nizard and Isabelle Petropoulos: All the cells in our body rely on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. Cells find it more and more difficult to preserve the stability of their proteome with time, which leads to progressive protein alteration and subsequently normal skin ageing.
There are many systems in skin that eliminate unfolded and/or non-functional proteins and we began our research by studying one of the most important of these, the proteasomes, which exist in cells and the nuclei of cells. This system is modified during ageing, exposure to ultraviolet rays and all types of oxidative stress (such as pollution and cigarette smoke to name but two). LON protease, which is similar to the proteasomes found in cells, exists in mitochondria.
There are only a few systems to repair proteins (in contrast to the many that repair DNA) since there are only two amino acids that can be repaired once they have been oxidized. One of these systems is known as PMSR or MSR (Methionine Sulfoxide Reductase). This system exists in skin and protects it against oxidative stress.
BD: Could you describe your work on MSR and how it led to your research on the glyoxalase system?
CN and IP: We studied skin cells that had been exposed to UV rays in vitro and found that MSR expression and activity decline with age and photo-exposition. It thus becomes less efficient and protects cells less well. We also studied models of reconstructed skin and found that when it was oxidized it reflects less light (that is, its reflectance is reduced - as measured with a radiance meter).
Based on these results, we developed a cosmetic product that makes use of an active ingredient called lipochroman, which is a powerful antioxidant analogue of vitamin E and a potent scavenger for reactive oxygen species (ROS) and reactive nitrogen species (RNS), produced by environmental elements like pollution or UV rays. Lipochroman boosts the activity of MSR.
The GLO system is another, well-known, detoxification and anti-glycoxidation system in the body, similar to proteasomes and MSR, but it acts on a different level since its action precedes these to eliminate certain components toxic to proteins. Recently, researchers also discovered that it plays an important role in animal longevity, so we thought it was important to study how this system behaves in human skin.
BD: Could you briefly explain your research on glyoxalase and the most important results you have obtained so far?
CN and IP: We are looking at how glyoxalase (GLO) acts to eliminate certain products of metabolism and oxidative stress, like dicarbonyls such as glyoxal (GO), which are toxic for proteins and cells. Until now, researchers were mainly familiar with the role this system plays in protecting against diabetic vascular complications or cardiovascular disease but its importance in detoxifying dicarbonyls inside skin cells themselves was less known.
GLO eliminates dicarbonyls and so protects cells from further oxidation. As mentioned, it is a detoxification system but until now, we did not know whether it existed in skin. Our work is the first to show that it indeed exists in normal human skin, proving that dicarbonyl stress does affect keratinocyte proteins as well. The intracellular glycation and glycoxidation induce alterations in cell function. The GLO system is thus crucial for preventing these alterations and preserving skin’s homeostasis.
BD: Where is glyoxalase found in skin and what function does it have?
CN and IP: It is found notably in epidermal keratinocytes and dermal fibroblasts. It appears to play the same protective role in protein homeostasis as the other systems we studied, especially in the basal layer of the epidermis. We also have preliminary results that indicate that glyoxalases might play an important role in the proliferation and differentiation of keratinocytes.
BD: Could you briefly describe the protective function of the GLO system?
CN and IP: The GLO enzymes, glyoxalase 1 (GLO1) and glyoxalase 2 (GLO2) eliminate and transform glyoxal (GO) and methylglyoxal (MGO), which are dicarbonyl compounds that come directly (for GO) and indirectly (for MGO) from the metabolism of glucose and other carbohydrates. GO and MGO are toxic for cells and react with intracellular proteins, modifying them and altering their function. GLO1 and GLO2 successively transform these into products that are less toxic – for example glycolate (for GO).
Thanks to its detoxifying role, the GLO system prevents GO and MGO from building up in cells, thus limiting protein damage, which is at the origin of cellular, and ultimately, tissue ageing.
BD: Could you describe your most important experiments?
CN and IP: Our in vitro studies of GLO in senescent keratinocytes and/or those obtained from aged subjects show that GLO1 activity significantly decreases (without its expression being modified) in these cells. This alteration in the system leads to a build-up of proteins that have been modified by GO and MGO. These proteins also build up in aged photo-exposed skin compared to non-photo-exposed skin, in particular in the dermis.
In contrast, the level of GO-modified proteins in these samples does not increase in the basal layer of the epidermis, where GLO1 is strongly expressed. The GLO system thus appears to protect proliferating cells against damage.