Partial depletion of mitochondrial DNA from human skin fibroblasts induces a gene expression profile reminiscent of photoaged skin.
In photoaged skin, wrinkles result from an increased degradation and a decreased de novo synthesis of collagen fibers. At the molecular level, photoaged skin is characterized by increased amounts of large-scale deletions of the mitochondrial (mt) genome such as the 4,977 bp common deletion. The common deletion can be generated in dermal fibroblasts through repetitive ultraviolet (UV) A irradiation, and this was found to be associated with an increased expression of the collagen-degrading enzyme matrix metalloproteinase-1 (MMP-1). These studies did not clarify whether increased MMP-1 expression was caused by a disturbance of mtDNA integrity or whether it occurred independently. We have therefore generated a phenocopy of cells bearing large-scale deletions of mtDNA by gradually depleting the mtDNA from unirradiated human skin fibroblasts. Gradual depletion of mtDNA caused a gene expression profile, which was reminiscent of that observed in photoaged skin. Accordingly, in these cells an increased expression of MMP-1 without a concomitant change in tissue inhibitor metalloproteinase-1 as well as a decreased expression of collagen type 1 alpha-1, that is, a gene involved in collagen de novo synthesis, was observed. This altered gene expression resulted from intracellular, mitochondria-derived oxidative stress. Our results support the concept that disruption of mt integrity, for example, by UV-induced mtDNA mutagenesis, is of pathogenetic relevance for photoaging of human skin.
Schroeder
Peter
P
Institut für Umweltmedizinische Forschung, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Gremmel
Tobias
T
Berneburg
Mark
M
Krutmann
Jean
J
D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004249:DNA Damage / Q000528:radiation effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004996:Ethidium / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015595:Skin Aging
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D020781:Matrix Metalloproteinase 1; D004996:Ethidium