Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice

Mohsen Hosseini; Walid Mahfouf; Martin Serrano-Sanchez; Houssam Raad; Ghida Harfouche; Marc Bonneu; Stephane Claverol; Frederic Mazurier; Rodrigue Rossignol; Alain Taieb; Hamid Reza Rezvani

doi:10.1038/jid.2014.511

Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice

J Invest Dermatol. 2015 Apr;135(4):1108-1118. doi: 10.1038/jid.2014.511. Epub 2014 Dec 1.

Affiliations

¹ Inserm U1035, Bordeaux, France; Université de Bordeaux, Bordeaux, France.
² Centre Génomique Fonctionnelle de Bordeaux, Université de Bordeaux, Bordeaux, France.
³ Inserm U1035, Bordeaux, France; Université de Bordeaux, Bordeaux, France; Centre de Référence pour les Maladies Rares de la Peau, CHU de Bordeaux, France.
⁴ Inserm U1035, Bordeaux, France; Université de Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), Bordeaux, France.
⁵ Inserm U1035, Bordeaux, France; Université de Bordeaux, Bordeaux, France; Centre de Référence pour les Maladies Rares de la Peau, CHU de Bordeaux, France; Département de Dermatologie and Dermatologie Pédiatrique, CHU de Bordeaux, France.
⁶ Inserm U1035, Bordeaux, France; Université de Bordeaux, Bordeaux, France; Centre de Référence pour les Maladies Rares de la Peau, CHU de Bordeaux, France. Electronic address: [email protected].

PMID: 25437426
DOI: 10.1038/jid.2014.511

Abstract

Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16(INK4a) expression, β-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc(-/-) mice than in young Xpc(+/+) ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc(-/-) was as low as in control aged Xpc(+/+)animals. Furthermore, the metabolic profile in young Xpc(-/-) mice resembled that found in aged Xpc(+/+) mice. Furthermore, premature skin aging features in young Xpc(-/-) mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
DNA-Binding Proteins / genetics*
Humans
Keratinocytes / cytology
Lamin Type A
Light
Mice
Mice, Knockout
Mitochondria / metabolism
NADH, NADPH Oxidoreductases / antagonists & inhibitors*
NADH, NADPH Oxidoreductases / metabolism*
NADPH Oxidase 1
Nuclear Proteins / metabolism*
Oxidative Stress
Protein Precursors / metabolism*
Proteins / genetics
Reactive Oxygen Species / metabolism
Skin Aging*
Xeroderma Pigmentosum / metabolism
beta-Galactosidase / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cdkn2a protein, mouse
Cyclin-Dependent Kinase Inhibitor p16
DNA-Binding Proteins
Lamin Type A
Noxa1 protein, mouse
Noxo1 protein, mouse
Nuclear Proteins
Protein Precursors
Proteins
Reactive Oxygen Species
Xpc protein, mouse
prelamin A
NADH, NADPH Oxidoreductases
NADPH Oxidase 1
NOX1 protein, mouse
beta-Galactosidase

Supplementary concepts

Xeroderma Pigmentosum, Complementation Group C