Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging

Abstract

Introduction:The analysis of the role of the mitochondria in oxidative damage and skin aging is a significant aspect of dermatological research. Mitochondria generate most reactive oxygen species (ROS); however, excessive ROS are cytotoxic and DNA-damaging and promote (photo-)aging. ROS also possesses key physiological and regulatory functions and mitochondrial dysfunction is prominent in several skin diseases including skin cancers. Although many standard dermatotherapeutics modulate mitochondrial function, dermatological therapy rarely targets the mitochondria. Accordingly, there is a rationale for "mitochondrial dermatology"-based approaches to be applied to therapeutic research.Areas covered: This paper examines the functions of mitochondria in cutaneous physiology beyond energy (ATP) and ROS production. Keratinocyte differentiation and epidermal barrier maintenance, appendage morphogenesis and homeostasis, photoaging and skin cancer are considered. Based on related PubMed search results, the paper evaluates thyroid hormones, glucocorticoids, Vitamin D3 derivatives, retinoids, cannabinoid receptor agonists, PPARγ agonists, thyrotropin, and thyrotropinreleasing hormone as instructive lead compounds. Moreover, the mitochondrial protein MPZL3 as a promising new drug target for future "mitochondrial dermatology" is highlighted.Expert opinion: Future dermatological therapeutic research should have a mitochondrial medicine emphasis. Focusing on selected lead agents, protein targets, in silico drug design, and model diseases will fertilize a mito-centric approach.

Diallyl disulfide induces DNA damage and growth inhibition in colorectal cancer cells by promoting POU2F1 ubiquitination

“…The imbalance between oxidation and antioxidant effects can lead to DNA damage in the body 21 . Wherein, oxidative DNA damage, particularly induced by reactive oxygen species (ROS), is one of the most common types of DNA damage in cells 21 , 22 . Accordingly, we examined whether DADS treatment could increase intracellular ROS levels in CRC cells.…”

Uncovering the impact of UV radiation on mitochondria in dermal cells: a STED nanoscopy study

“…Mitochondria play a central role in maintaining cellular energy metabolism and various cellular functions, and their dysfunction is related to UV-induced cellular damage and photoaging [26][27][28] . While the overall architecture and major functions of mitochondria have been described progressively, the relationship between mitochondria and aging remains poorly understood.…”

Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo

“…Mitochondrial dysfunction plays a crucial role in skin aging [33,63,[73][74][75], leading us to also investigate the impact of melatonin on the expression of the key mitochondrial proteins cytochrome c oxidase I (MTCO-1) and mitochondrial transcription factor (TFAM), which control mitochondrial biogenesis and DNA synthesis [21][22][23]. We also examined voltage-dependent anion channel VDAC/Porin expression, as a useful screening marker for mitochondrial abundance.…”

“…Specifically, we asked whether the "systemic" administration of high-dose melatonin (100 µM and 200 µM) [45] significantly changes epidermal S6 phosphorylation (a direct marker of mTORC1 activity [51]), collagen 17A1 (the key stem-cell-niche-associated transmembrane matrix molecule [52][53][54]), Matrix Metalloproteinase 1 (MMP-1, the activity of which is associated with degradation of collagen I and collagen III fibers [55]). We also assessed the protein immunoreactivity of sirtuin-1 ((SIRT-1), which takes part in deacetylation of key substrates-histones or p53-involved in the regulation of cell metabolism and cell cycle [56]), of lamin-B1 (the main component of nuclear lamina stabilizing the nucleus [57,58]), p16 INK4 (tumor suppressor promoting the senescence in cell cycle [59,60]), γH2A.x (phosphorylated histone protein H2A.x, a marker of double-strand breaks in DNA [61]), the mitochondrial markers TFAM, MTCO-1, and VDAC/Porin, since mitochondrial dysfunction is associated with aging [33,47,62,63], and the recently identified key driver of human skin rejuvenation, VEGF-A [3,17]. In the dermis, we analyzed protein expression of fibrillin-1 and collagen I, matrix proteins produced by fibroblasts, the reduced production and increased degradation of which produce key clinical features of skin aging like wrinkle formation and loss of elasticity [64,65].…”