Oxidative stress and mitochondrial dysfunction in Kindler syndrome
Zapatero-Solana, Elisabeth (Universidad Carlos III de Madrid)
García-Giménez, José Luis (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Guerrero-Aspizua, Sara (Universidad Carlos III de Madrid)
García, Marta (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Toll, Agustí (Institut Hospital del Mar d'Investigacions Mèdiques)
Baselga Torres, Eulàlia (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Durán-Moreno, Maria (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Markovic, Jelena (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
García-Verdugo, José Manuel (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Conti, Claudio J. (Universidad Carlos III de Madrid)
Has, Cristina (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Larcher, Fernando (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Pallardó, Federico V. (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Del Rio, Marcela (Universidad Carlos III de Madrid (UC3M))
Universitat Autònoma de Barcelona

Data:	2014
Resum:	BACKGROUND: Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease. METHODS: Patient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy. RESULTS: Patient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state. CONCLUSIONS: This is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.
Ajuts:	Ministerio de Ciencia e Innovación PI11/01225 Ministerio de Ciencia e Innovación SAF2010-16976
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Adolescent ; Aged, 80 and over ; Blister ; Cells, Cultured ; Child ; Child, Preschool ; Epidermolysis Bullosa ; Female ; Humans ; Keratinocytes ; Male ; Middle Aged ; Mitochondria ; Oxidative Stress ; Periodontal Diseases ; Photosensitivity Disorders
Publicat a:	Orphanet journal of rare diseases, Vol. 9 (2014) , p. 211, ISSN 1750-1172

DOI: 10.1186/s13023-014-0211-8
PMID: 25528446

10 p, 2.6 MB

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