Altered MCM Protein Levels and Autophagic Flux in Aged and Systemic Sclerosis Dermal Fibroblasts

• Published in: Journal of investigative dermatology Vol. 134; no. 9; pp. 2321 - 2330
• Main Authors: Dumit, Verónica I., Küttner, Victoria, Käppler, Jakob, Piera-Velazquez, Sonsoles, Jimenez, Sergio A., Bruckner-Tuderman, Leena, Uitto, Jouni, Dengjel, Jörn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014; Elsevier Limited
• Subjects: Adolescent; Adult; Aged; Autophagy - physiology; Cells, Cultured; Child, Preschool; Dermis - cytology; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Infant, Newborn; Male; Middle Aged; Minichromosome Maintenance Complex Component 7 - genetics; Minichromosome Maintenance Complex Component 7 - metabolism; Phenotype; Proteomics; RNA, Messenger - metabolism; Scleroderma, Systemic - genetics; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - pathology; Skin Aging - physiology; Young Adult
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1038/jid.2014.69

Aging is a common risk factor of many disorders. With age, the level of insoluble extracellular matrix increases leading to increased stiffness of a number of tissues. Matrix accumulation can also be observed in fibrotic disorders, such as systemic sclerosis (SSc). Although the intrinsic aging process in skin is phenotypically distinct from SSc, here we demonstrate similar behavior of aged and SSc skin fibroblasts in culture. We have used quantitative proteomics to characterize the phenotype of dermal fibroblasts from healthy subjects of various ages and from patients with SSc. Our results demonstrate that proteins involved in DNA and RNA processing decrease with age and in SSc, whereas those involved in mitochondrial and other metabolic processes behave the opposite. Specifically, minichromosome maintenance (MCM) helicase proteins are less abundant with age and SSc, and they exhibit an altered subcellular distribution. We observed that lower levels of MCM7 correlate with reduced cell proliferation, lower autophagic capacity, and higher intracellular protein abundance phenotypes of aged and SSc cells. In addition, we show that SSc fibroblasts exhibit higher levels of senescence compared with their healthy counterparts, suggesting further similarities between the fibrotic disorder and the aging process. Hence, at the molecular level, SSc fibroblasts exhibit intrinsic characteristics of fibroblasts from aged skin.