Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis

Abstract

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as “innate pathogen” triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non‐lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at −80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin‐related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non‐lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.

Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes

“…Taurine is an essential compound for keratinocyte hydration and for protection of keratinocytes from osmotically and UV-induced apoptosis, 53,54 AFG1L, which interacts with psoriasis risk variants, functions in mitochondrial protein homeostasis, and dysregulation of mitochondria may trigger inflammation and reduces apoptosis in keratinocytes. 55 Thus, these GWAS risk variants interact with promoters of genes found to be associated with skin diseases via functional studies, which confirms the relevance of our work in mapping target genes of risk variants. It is important to note that we included all reported GWAS variants in our analysis.…”

NIX initiates mitochondrial fragmentation via DRP1 to drive epidermal differentiation

“…These differentiation-specific sub-cellular structures have long been ascribed a role in skin barrier function and have been shown recently to drive liquid-liquid phase separation to facilitate cell flattening during keratinocyte differentiation ( Quiroz et al, 2020 ). Moreover, loss of KH granules has been associated with skin disorders, including ichthyosis vulgaris and psoriasis, with the latter being linked to impaired autophagic flux and mitochondrial dysfunction ( Akinduro et al, 2016 ; Brody, 1962 ; Douroudis et al, 2012 ; Therianou et al, 2019 ). The potential to target autophagy ( Levine et al, 2015 ; Markaki et al, 2018 ) or mitochondrial dynamics ( Lackner and Nunnari, 2010 ) for clinical benefit is under investigation and could be leveraged to treat dermatological disease ( Guo et al, 2019 ; Yanagi et al, 2018 ) and even delay skin aging ( Singh et al, 2018 ; Zhao et al, 2017 ).…”

Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

“…Psoriasis is another disease in which DNA-induced inflammation is involved. Increased cell-free DNA and mtDNA were detected in the serum of psoriatic patients ( 215 , 216 ). The topical skin application of imiquimod, a TLR7 ligand, is used to induce psoriasis in mice.…”