Can Mitochondrial Dysfunction Explain a Range of Skin Disorders and Aging?

🔍 Key Finding Mitochondrial dysfunction, including DNA damage and altered activity, is implicated in various dermatologic conditions like premature skin aging, hair loss, impaired wound healing, and inflammatory skin diseases such as lupus, psoriasis, vitiligo, and atopic dermatitis. Mouse models suggest some of these effects, like hair loss and skin aging, may be reversible with restoration of mitochondrial function, highlighting mitochondria as a potential therapeutic target.

🔬 Methodology Overview

• Design: Narrative review
• Data Sources: PubMed and Embase, with subsequent hand-searching for additional articles.
• Selection Criteria: Studies of any type (including murine and in vitro) assessing the relationship between mitochondrial dysfunction and dermatologic conditions/outcomes. No date restriction, though preference given to recent publications.
• Analysis Approach: Qualitative synthesis of findings from retrieved articles.
• Scope: Dermatologic manifestations of mitochondrial dysfunction, including aging, hair loss, wound healing, and specific skin disorders (lupus, psoriasis, vitiligo, atopic dermatitis, skin cancer).

📊 Results

• Chronological Aging: Age-dependent increase in a 4977 bp mtDNA deletion in normal skin; decreased mitochondrial membrane potential and increased ROS levels in older fibroblasts; age-related decrease in fibroblast complex II activity; age-related impairment in Coenzyme Q10.
• Photoaging: 10-fold increase in the common mtDNA deletion in photoaged vs. sun-protected skin; prior UV exposure increases susceptibility to UVA-induced mtDNA deletions; mtDNA-depleted fibroblasts show increased collagen-degrading enzymes and decreased collagen synthesis genes.
• Wound Healing: Stage-specific mitochondrial metabolism changes in macrophages during wound healing; mitochondrial dysfunction associated with delayed wound healing in diabetic mice.
• Systemic Lupus Erythematosus (SLE): SLE T cells exhibit excessive ROS production, low glutathione and ATP, and hyperpolarized mitochondrial membranes; oxidized mitochondrial nucleoids accumulate and trigger interferon responses; defective mitochondrial removal in SLE erythropoiesis.
• Psoriasis: Decreased expression of mitochondrial function regulators (uncoupling protein 2, dynamin-related protein 1, calcineurin) in psoriatic lesions; imiquimod-induced psoriasis increases mitochondrial ROS and inflammatory cytokine production.
• Vitiligo: Impaired mitochondrial ATP production and increased proton leak in vitiligo melanocytes; perilesional vitiligo skin shows fewer, larger, and irregularly structured mitochondria with defective TCA cycles and increased ROS.
• Atopic Dermatitis (AD): Impaired NRF2-antioxidant pathway and decreased mitochondrial proteins in AD; increased mitochondrial activity, ROS levels, and proton leak in non-lesional AD keratinocytes.
• Hair Loss: mtDNA depletion leads to hair loss in mice, reversible upon restoring mitochondrial function; hair follicle stem cell differentiation activates mitochondrial respiration, and inhibiting this impairs hair regeneration.

💡 Clinical Impact Mitochondrial dysfunction plays a significant role in various skin conditions including aging, hair loss, impaired wound healing, and inflammatory disorders like lupus, psoriasis, vitiligo, and atopic dermatitis, suggesting that targeting mitochondrial function may offer novel therapeutic strategies for these conditions. This could lead to the development of new treatments focused on improving mitochondrial function, such as targeted antioxidants or mitochondrial transplantation, to address a range of dermatological issues.

🤔 Limitations

• Limited data on the precise mechanism of mitochondrial-mediated wound healing.
• Causality between mitochondrial dysfunction and dermatologic outcomes not fully established in humans.
• Limited data on long-term efficacy of mitochondrial-targeted therapies.
• Conflicting findings regarding mtDNA copy number as a biomarker in psoriasis.
• Limited understanding of mitochondrial involvement in skin cancer development.
• Further research needed on the clinical translation of mitochondrial transplantation for hair loss.
• Most studies on mitochondrial dysfunction in dermatological conditions rely on in vitro or mouse models.

✨ What It Means For You This research suggests that mitochondrial dysfunction plays a significant role in various skin conditions, including aging, wound healing, and inflammatory disorders like lupus and psoriasis. This understanding may lead to the development of new therapeutic strategies targeting mitochondrial function for improved treatment outcomes in dermatology. Doctors may consider mitochondrial-targeted therapies, such as antioxidants or transplantation, for patients with these conditions.

Reference Natarelli N, Gahoonia N, Aflatooni S, Bhatia S, Sivamani RK. Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature. Int. J. Mol. Sci. 2024;25:3303. https://doi.org/10.3390/ijms25063303