The importance of mitochondria targeting molecules (MTM) in cell survival and subsequently in fighting skin burnout and advanced skin aging

The human skin is a high turnover organ. Its constant renewal depends on the rapid proliferation of its progenitor cells. The energy requirement for these metabolically active cells is met by the most important organelles in cells, the mitochondria. (4*)

On the one hand, mitochondria synthesize adenosine triphosphate (ATP), the energy required to maintain cell viability; on the other hand, damaged mitochondria produce reactive oxygen species (ROS), cytochrome c and other signals, which initiate apoptosis (cell death) by activating caspase family proteins. (7*)

The amount of ATP that human beings require to go about their lives is staggering. A sedentary male of 70kg requires about 2000 kcal for a day’s worth of activity. To provide this much energy requires 83kg of ATP. However, human beings possess only about 250g of ATP at any given moment. The disparity between the amount of ATP that we have and the amount that we require is compensated by recycling ADP back to ATP. Each ATP molecule is recycled approximately 300 times per day. (1*)

If the mitochondria do not have energy, it will go through apoptosis (cell death). It would be logical to conclude that the mitochondria’s lack of energy, or inability to provide energy, can then be considered a cause of skin aging. The number of mitochondria in a cell is directly related to the activity of the cell. (2*)

Electron microscopic studies revealed that mitochondria have two membrane systems: an outer membrane and an extensive, highly folded inner membrane.

(Fig. 1 Electron micrograph of a mitochondrion; Source: CFCF via Wikimedia Commons)

The inner membrane is folded into a series of internal ridges called cristae. Hence, there are two compartments in mitochondria: Firstly, the intermembrane space between the outer and the inner membranes and secondly, the matrix which is bounded by the inner membrane. The mitochondrial matrix is the site of most of the reactions of the citric acid cycle (also called Krebs cycle) and fatty acid oxidation. In contrast, oxidative phosphorylation takes place in the inner mitochondrial membrane. (1*)

(Fig. 2 Diagramtic structural features of a mitochondrion; Source; Kelvinsong via Wikimedia Commons)

Mitochondria, long considered to have the primary role in cellular energetic processes, have been the center of much research interest in the recent past.

Technological advances in microscopy and development of new and specific fluorescent dyes for visualization of mitochondrial dynamics in living cells have facilitated the newfound interest in these fascinating organelles, which are now implicated in diverse cellular functions crucial in health and disease.

Mitochondria play crucial roles in several age-related diseases, and in the physiology of normal aging. (3*)

This double membrane-bound organelle is involved in essential functions like energy production, fatty acid oxidation (FAO), heme and steroid biosynthesis, apoptosis and calcium signaling. Recent studies have established an essential role of the mitochondria in skin homeostasis, as well as in disorders such as cancer, inflammatory conditions, and rare inherited diseases. (4*)

In addition to skin aging and cancer, mitochondrial dysfunction has also been associated with various common and rare skin disorders that can be broadly classified into three types: dermal manifestations of primary mitochondriopathies, skin diseases due to mitochondrial dysfunction and cutaneous manifestations of genetic diseases that affect mitochondria. Clinically, these disorders can be present as hair abnormalities, inflammation, rashes, hypo- and hyperpigmentation etc. (4*)

The structural and functional manifestations of cutaneous aging are premature and more severe in the photo-aged compared to the chronologically aged skin. Both intrinsic and environmental factors affect the epidermal and dermal layers of the skin. Several studies have directly or indirectly linked mitochondrial dysfunction to both chronological and photo-aging of the skin. At the molecular levels, aged skin is characterized by damaged mitochondria, mtDNA deletions, high ROS levels, and oxidative stress in both the dermal and epidermal layers.

Chronological skin aging mutations and deletions in mtDNA are known to accumulate in post-replicative tissues with aging, which is accompanied by a steady decline in mitochondrial function, increased ROS production, and loss of mitochondrial membrane potential (MMP), followed by increased mitophagy, and apoptosis. (4*)

Not surprisingly, the mitochondria are the primary organelle affected during chronological and UV-induced skin aging, the phenotypic manifestations of which are the direct consequence of mitochondrial dysfunction. With studies increasingly supporting the close association between mitochondria and skin health, its therapeutic targeting in skin – either via an ATP production boost or free radical scavenging – has gained attention. (4*)

Additionally, oxidative damage because of mitochondrial generation of reactive oxygen species (ROS) can lead to accelerated aging. (3*)

Other findings demonstrate that repeated exposure to sub-lethal doses of UVA resulted in mtDNA deletions in primary human keratinocytes and dermal fibroblasts, which was accompanied by decreased mitochondrial function, increased activity of collagen-degrading enzymes and oxidative stress, which further exacerbated the mitochondrial damage. (4*)

As mitochondria become amenable as a target for medicine, we would also see these organelles as an important target for skin care, especially in the anti-aging sector.

It is reasonable to expect that skin care products boosting and protecting mitochondrial functions will provide skin benefits such as oxidative defense, cell survival, improved skin barrier and protection from daily environmental assaults, including sun bed use and rejuvenation of skin appearance. (3*)

Mitochondria are particularly susceptible to ROS and subsequent DNA damage as they are a major intracellular source of oxidants. Therefore, the development of mitochondrially targeted agents to mitigate mitochondrial oxidative stress and resulting DNA damage is a logical approach to prevent and treat UV-induced skin damage. Protecting and boosting the mitochondrial components unquestionably provide stress protection to cells. (5*)

Drugs targeting mitochondria to inhibit mitochondrial damage and resolve abnormal mitochondrial functions are expected. Thereby, several human diseases require such therapeutic interventions even in diseases not originally caused by mitochondrial damage. One mitochondria-targeting approach is antioxidants treatment to decrease the oxidative damage caused by reactive oxygen species (ROS). (8*)

Since the mitochondrion is a major site that produces ROS by oxidative phosphorylation, mitochondria-targeted antioxidants can effectively minimize mitochondrial dysfunction and improve related diseases. (6* & 9*)

Mitochondria are involved in many pathologies due to their crucial roles in energy generation, cellular metabolism, and cellular apoptosis. Therapeutic investigations based on mitochondria targeting are providing exciting new approaches to disease treatment and drug discovery. Thus, various strategies for mitochondrial drug targeting are being developed, e.g. sorbitol-based molecular transporters (6*), specially selected antioxidants as radical scavengers, polyphenols and others.

SUMMARY

Mitochondria generate most of the ATP required by aerobic cells through a joint endeavor of the reactions of the citric acid cycle (Krebs cycle), which take place in the mitochondrial matrix and oxidative phosphorylation, which takes place in the inner mitochondrial membrane. Intrinsic and extrinsic stress factors such as chemicals, UV-exposure etc. lead to a high increase in ROS-formation and eventually to a decrease in ATP-production and finally accelerating skin ageing and apoptosis (cell death). Advanced technologies and new findings in mitochondrial activity and health suggest a more specific and targeted treatment of mitochondria. The development of Mitochondria-targeting molecules (MTM) is already ongoing in the pharmaceutical field showing first promising results, e.g. in cancer treatment. The development and use of MTM in skin care has become of big interest as the protection of mitochondria from further damage is essential for keeping skin healthy and young-looking, to prevent skin-burnout and finally slow down skin ageing process. [written by jw-partner.ch]

References:

(1*) Berg, J. M, et al., (2018). BIOCHEMISTRY 8th edition.

(2*) Wade, S., (2018). Bioactive Peptides and the Mitochondria. https://www.dermascope.com/skin-care/9874-bioactive-peptides-and-the-mitochondria, retrieved 14.01.2023.

(3) Menon, G.K., et al., (2010). Mitochondria: a new focus as an anti-aging target in skin care. Journal of Cosmetic Dermatology, 2010 Jun;9(2):122-31.

(4*) Sreedhar, A., Aguilera-Aguirre, L., Singh, K., (2020). Mitochondria in skin health, aging, and disease. Cell Death and Disease, 11(6).

(5*) Brand, R. M., et al., (2018). Targeting Mitochondrial Oxidative Stress to Mitigate UV-Induced Skin Damage, Frontiers of Pharmacology, 9:920.

(6*) Murthy, A. S. N., et al., (2022). Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex. Drug Delivery, 2022 Dec;29(1):270-283.

(7*) Chan, D. C. (2006). Mitochondria: Dynamic Organelles in Disease, Aging, and Development. Cell 125 (7), 1241–1252.

(8*) Hoye et al., (2008). Targeting mitochondria. Acc Chem Res. 2008 Jan;41(1):87-97.

(9*) Battogtokh G, et al., (2018). Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives. Acta Pharm Sin B. 2018 Oct;8(6):862-880.