Partial Depletion of Mitochondrial DNA from Human Skin Fibroblasts Induces a Gene Expression Profile Reminiscent of Photoaged Skin

Abstract

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.

Human Mitochondrial DNA Polymerase γ Exhibits Potential for Bypass and Mutagenesis at UV-induced Cyclobutane Thymine Dimers

“…Photoaging of the skin has been closely tied to mtDNA mutations and deletions (36,53,54), and there is recent evidence associating mtDNA damage with several types of skin cancer (55)(56)(57)(58)(59). A handful of studies that have tested mtDNA from melanoma and non-melanoma skin cancer patients have revealed a number of A 3 G and T 3 C point mutations (56,57,59), often in the context of pyrimidine:pyrimidine dimers.…”

Functional Consequences of Mitochondrial DNA Deletions in Human Skin Fibroblasts

“…These observations further support the concept that UVinducible large scale deletions of mtDNA are of functional relevance for photoaging of human skin. 16,54,55 Indeed, separate studies using KSS-containing dermal equivalents, which in contrast to the present study have been analyzed at later time points (Ͼ4 day-old dermal equivalents), indicate that KSS-containing dermal equivalents show several more features that are highly characteristic of photoaged human skin (Krutmann et al, manuscript in preparation).…”

Pluripotent stem cells and mitochondrial dysfunction

“…In addition, ρ˚ cells have decreased levels of cell proliferation, mitotic cyclin gene expression, cyclin-dependent kinase inhibitors, retinoblastoma 1 phosphorylation, and telomerase activity [62,63]. In ρ˚ cells, upregulation of mitochondrial biogenesis-related genes, relative to expression in control cells, has been observed [64,65].…”