Each organ in the human body plays an important and unique function. Similar to the organs in the body, our cells contain a compilation of distinctive organelles, each playing an important role in the health and function of the cell. The mitochondria are of particular importance to cell health as they function primarily to produce adenosine triphosphate (ATP), the energy of the cell. It is almost as if they are the lungs of the cell, driving cell respiration. Looking at the cellular metabolism at the mitochondrial level and how their improper function can have negative ramifications on skin health allows a unique perspective on how skin changes throughout time (intrinsically) and when exposed to different conditions (extrinsically). The skin care industry is currently engaged in research to determine the best ways to harness mitochondrial functions for use in the fight against premature aging and skin cancer and to provide clues on winning the ongoing quest for healthy, youthful skin.
The Engines of the Cell
Mitochondria are known as the powerhouses of cells, the main function of these complex oval-shaped mitochondria is cellular respiration (oxidative metabolism or oxidative phosphorylation). Dependent on what type of function a specific cell performs in the body, some contain only one mitochondrion while others contain thousands. During cellular respiration, the mitochondria generate energy for the cell as a whole by processing the nutrients we ingest into charged molecules, ultimately producing ATP molecules. ATP provides energy for most activities within the cell. Additionally, mitochondria contribute to other cellular functions including the cell cycle, cell growth, apoptosis (cell death), cell differentiation and thermogenesis (heat production).
Mitochondria have two membranes made of phospholipids and proteins. The outer membrane of mitochondria is smooth and semi-permeable, allowing only small molecules and ions to come in and out. The inner membrane is permeable to oxygen, carbon dioxide and water, and is folded many times over. These folds are known as cristae, which encompass more surface area in order for chemical reactions to take place. Molecules and enzymes that create ATP reside on and within the folds of the cristae. The inter-membrane space is made up of a gel-like matrix that consists of a mixture of water and two-thirds of all of the proteins contained in the mitochondria. The enzymes that catalyze the reactions of respiration (ATP) are components of both the gel-like matrix and the inner mitochondrial membrane. The gel-like matrix space contains mitochondrion-specific DNA (mtDNA), ribonucleic acid (RNA) and ribosomes that participate in the synthesis of several mitochondrial components.
The Negative Effects of Metabolism
The process of cell metabolism, or respiration, is one that is prone to errors and ultimately leads to the production of reactive oxygen species (ROS), a set of highly active free radicals. The mitochondria are the sites of the highest ROS production in the cell, exposing the mtDNA to oxidative damage. The repair mechanisms available for mtDNA are limited and the mutational rate of mtDNA is approximately 50 times higher than that of nuclear DNA. mtDNA mutations may play a major causative role in the normal aging process. As mtDNA mutations accumulate, the normal function of the mitochondria declines. These mutations are now seen as culpable in the process of, and are potential markers for, photoaging.
Accumulation of oxidative damage caused by ROS and mutations of DNA lead to what we consider characteristic signs of aging, including the development of fine lines and wrinkles, decreased or impaired barrier function, and loss of skin tissue. These macro aspects are direct consequences of the loss of mitochondrial enzymatic activity. A specific signaling cascade results in an increase in (MMP-1), or interstitial collagenase, expression. Although MMP enzymes are necessary to recycle spent proteins, this upregulation leads to the degradation of healthy collagen, resulting in cutaneous aging. The damaged proteins accumulate within the mitochondria while the process of converting nutrients into ATP (oxidative phosphorylation) decreases, leading to a reduction in cellular energy synthesis. All of these outcomes in concert result in further physiological failures. The occurrence of apoptosis as a result of mitochondrial dysfunction has been linked to organ malfunction, skin diseases, cancer and aging.
DNA Damage
In genetics, the term ‘deletion’ refers to a DNA mutation where a sequence is missing, potentially leading to disease. ‘Common deletion’ is a term that represents a 4977 base pair deletion of mtDNA. This is a large loss of genetic material and can happen either because the parent molecule is damaged or mutated when it attempts to replicate, or as a result of an error during replication. The epidermal keratinocytes in the skin have been found to be particularly sensitive to the decline of mitochondrial function and mtDNA mutations when exposed to ultraviolet (UV) radiation. This common deletion of mtDNA is increased up to ten-fold in photoaged skin compared to sun-protected skin in the same individuals. [1] Additionally, it has been shown that two weeks of sun exposure (particularly UVA radiation) leads to an approximate 40 percent increase in the levels of common deletion in the dermis, which persists for at least 16 months.[2]
Protecting the Cells
Due to the prominent role of mitochondrial function in both intrinsic and extrinsic aging, the skin care industry is actively looking into the many ways mitochondria might play a role in skin health in general and anti-aging specifically. Protecting mitochondria from UV-induced damage, particularly UVA-generated mtDNA mutations, is an important step that can be achieved with year-round, daily use of broad spectrum UVA/UVB sunscreens and by following recommended sun protection measures, like wearing protective clothing and sun avoidance between 10 a.m. and 4 p.m.[3] Anthocyanins and some other plant pigments have also been shown to exhibit UV-protective effects on human skin cells, representing a useful addition to mitochondria-protecting regimens.
In terms of fighting signs of aging by targeting skin cells and the mitochondria specifically, topically applied antioxidants are effective in fighting intrinsically accumulated ROS that stem from normal mitochondrial function, and in preventing mitochondria-induced MMP-1 expression and consequent deterioration of the extracellular matrix. Antioxidants are molecules capable of scavenging ROS through multiple mechanisms. The most documented as having potent antioxidative properties and the most widely used for skin care and skin protection purposes include L-ascorbic acid, tocopherol and polyphenols (resveratrol, silymarin, green tea extract and grape seed extract, et cetera). Coenzyme Q 10 is another ingredient that has been shown to improve mitochondrial function and efficacy, as well as performing as an antioxidant. [4]
Niacinamide is a coenzyme precursor for important redox coenzymes – nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+) – and their reduced forms, NADH and NADPH, respectively. These coenzymes play important roles in many enzymatic reactions, which at least partially explains the exceptionally broad spectrum of effects that topical niacinamide exhibits on skin. Among those multiple effects, niacinamide has been shown to decrease ROS production by mitochondria and to extend the replicative lifespan of fibroblasts [5], an effect that points to the boosting of mitochondrial function and the protection of the mitochondrial genome.
Aconitase is a crucial enzyme in the citric acid cycle that is specifically altered by oxidative damage, resulting in a loss of catalytic function and, consequently, to a decline of mitochondrial function. If active ingredients can be designed to stimulate aconitase enzyme activity in mitochondria to prevent the ever-increasing damage from cellular oxidative stress, beneficial anti-aging possibilities for personal skin care are conceivable.
Given the significant role mitochondria and their metabolism play in the aging process, it is not surprising that the skin care industry is focusing significant efforts on developing products which will protect mitochondria and boost their function. Such products will contribute to increased skin cell protection, longer cellular life, improved barrier function and a better functioning extracellular matrix, leading to healthy, more youthful skin.
CITATIONS
- Koch H., Wittern KP, Bergemann J., J Invest. Dermatol, 2001, 117; 892-7.
- Berneburg M., Plettenberg H., Medve-Konig K., Pfahlberg A., Gerls-Barlag H., Geffeler O., Krutmann J., J Invest. Dermatol, 2004, 122; 1277-83.
- FDA 2011
- Prahl S et al., Biofactors, 2008, 245-55.
- Kang HT, Hwang ES, Aging Cell, 2008, 8, 426-38; Matts PJ, Oblong JE, Bisset DL. A, Int. Fed. Soc. Cosmet. Chem. Mag., 2002, 285-9.
RESOURCES
- http://onlinelibrary.wiley.com/doi/10.1111/j.1473-2165.2010.00496.x/pdf
- Voet & Voet, Biochemistry, John Willey & Sons, Inc. 1995
- Elsner P et al, JDDG, 2011, 9, Suppl 3 S1-S32
Ivana Veljkovic, PhD, manages product development, regulatory and clinical trials for PCA Skin. She received her doctorate in organic chemistry from Freie Universität Berlin, and her master’s of science degree in chemistry from the University of Belgrade in Yugoslavia. Veljkovic has previously worked as a research scientist specializing in the synthesis and purification of organic compounds before joining a health care company in Canada that represented PCA Skin. In her role, she worked directly with physicians, nurses and estheticians, educating them about skin physiology, ingredients and proper treatments for specific skin conditions.
