Retrograde signaling responses in extrinsic skin aging

• Applicant: Professor Dr. Jean Krutmann
• Subject Area: Dermatology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 228001563

Photoaging of skin is thought to result from two completely different types of biological responses: (i) acute stress responses which are transient in nature and (ii) chronic, permanent responses, which are due to the accumulation of damaged macromolecules. The final clinical outcome may be identical in both cases and e.g. include an increased expression and activation of collagen degrading matrixmetalloproteinases which contribute to wrinkle formation. The signaling cascade involved in acute stress responses has been well characterized. In this regard it has been shown that such responses are not only initiated by UVB or UVA, but also by infrared (IR) A-radiation. In particular, we have previously shown that IRA radiation primarily acts on mitochondria in dermal fibroblasts where it initiates a signaling response traveling from the mitochondria to the nucleus and which ultimately affects the fibroblast transcriptom e.g. by increasing the transcriptional expression of MMP-1. This response which starts intramitochondrially thus represents a retrograde signaling response, as opposed to anterograde responses which are initiated in the nucleus. Interestingly, retrograde signaling responses in dermal skin fibroblasts are also involved in skin aging caused by the accumulation of mt DNA deletions. In contrast to the response elicited by IRA radiation, which only transiently impacts on mt functions, the presence of mt DNA deletions causes a permanent alteration of mt integrity. In both cases, however, the resulting response increases MMP-1 expression and activity. Little is currently known about the single components and steps involved in the signaling response which is initiated through the accumulation of mt DNA deletions. In addition, it is not known whether and how these two types of retrograde mitochondrial responses influence each other and how this interaction affects photoaging of human skin. Hypothesis: Transient and permanent disturbances of mt integrity cause different types of retrograde mitochondrial signaling responses in dermal skin fibroblasts which in combination act in an additive or synergistic manner and thereby lead to enhanced/accelerated photoaging of human skin. Goals: In order to test this hypothesis we will work on the following two topics: (i) analysis and comparison of the two types of retrograde mitochondrial responses mentioned above, i.e. the transient response elicited by acute IRA irradiation versus the persistent one caused by the presence of mt DNA deletions in primary human skin fibroblasts; (ii) analysis of the signaling response which is initiated in skin fibroblast in which both responses are elicited with special emphasis on the clinical relevance of this interaction for photoaging of human skin.

• DFG Programme: Research Grants