Keio University led group clarify that intracellular magnesium ions protect the skin from oxidative stress

Human skin is constantly exposed to reactive oxygen species generated by ultraviolet light, and this oxidative stress is said to cause skin aging, inflammation, and various diseases. Although magnesium ions are known to promote the growth of skin cells and restore skin barrier function, their dynamics within the skin cells and their role in skin barrier function remained unclear.

Graduate Student Keigo Fujita of the Graduate School of Science and Technology at Keio University (at the time of research), Professor Kotaro Oka of the School of Frontier Engineering at Kitasato University (Professor of Keio University), Associate Professor Kohji Hotta and Senior Assistant Professor Yutaka Shindo of the Faculty of Science and Technology at Keio University, in collaboration with Dr. Yuji Katsuta and Dr. Makiko Goto of MIRAI Technology Institute at Shiseido, discovered that the intracellular concentration of magnesium ions increases in human keratinocytes (epidermal cells in the skin barrier layer) exposed to reactive oxygen species, and this increases the mitochondrial energy-producing process in the cell, which has the effect of protecting against oxidative stress. The findings were published in the August 24, 2023 issue of the scientific journal Communications Biology.

The research group used fluorescence imaging to study in detail the changes in intracellular magnesium ion concentrations when keratinocytes (which make up the majority of the skin's epidermis) are exposed to hydrogen peroxide, a type of reactive oxygen species. They found that the intracellular magnesium ion concentration gradually increased in keratinocytes exposed to hydrogen peroxide. Additionally, these changes in magnesium ion concentration were more pronounced in keratinocytes derived from adults than in those obtained from newborns.

In newborn-derived keratinocytes, where the adenosine triphosphate (ATP) level does not tend to decrease, the magnesium ion concentration is less likely to increase. By contrast, in keratinocytes with inhibited ATP generation, the magnesium ion concentration increases greatly. Therefore, in cells exposed to hydrogen peroxide, the decrease in ATP concentration may cause an increase in magnesium ion concentration.

In cells, many magnesium ions bind strongly to ATP to form complexes. When ATP is consumed, the bound magnesium is released as ions, leading to an increase in the intracellular magnesium ion concentration. In keratinocytes under oxidative stress, a large amount of ATP is consumed, resulting in the release of magnesium ions.

The researchers also examined the relationship between oxidative stress-induced mitochondrial damage and magnesium ions. Because oxidative stress inhibits mitochondrial function, a decrease in the mitochondrial membrane potential is a damage indicator. The researchers used simultaneous fluorescence imaging to compare the changes in the magnesium ion concentration and mitochondrial membrane potential. The results revealed that the hydrogen peroxide-induced decrease in the mitochondrial membrane potential was small in cells with a large increase in the magnesium ion concentration, whereas the decrease was large in cells with a small increase in magnesium ion concentration.

Next, the researchers increased the intracellular concentration of magnesium ions by supplementing the cell culture medium with a solution containing the ions, which diffuse into the cells. They found that the decrease in the mitochondrial membrane potential could be further suppressed by the increased concentration of magnesium ions within the cells.

The results showed that intracellular magnesium ions suppressed hydrogen peroxide-induced mitochondrial damage in a concentration-dependent manner, indicating that magnesium ions protect the mitochondria. This is due to the formation of a feedback loop in which magnesium ions liberated by the generation of a large amount of ATP in response to reactive oxygen species protect the mitochondria, the key organelles for ATP generation. The additional effect mediated by the magnesium ions taken up from outside the cells indicates the potential of magnesium ions as an active antioxidative ingredient.

Journal Information
Publication: Communications Biology
Title: Intracellular Mg²⁺ protects mitochondria from oxidative stress in human keratinocytes
DOI: 10.1038/s42003-023-05247-6