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.