Upon aging, all organs of the body suffer from a progressive impairment in structure, morphology and function due to intrinsic factors. This contributes to a wide variety of skin alterations and pathologies such as skin atrophy and wound healing problems. The skin, as the outermost organ, acts as an external barrier that is exposed not only to such intrinsic, but also to extrinsic factors. The most common cause for external aging is UV irradiation (photoaging), which worsens and accelerates the aging process. Ultimately, long-term photoaging effects contribute to the formation of malignant skin tumors.
The accumulation of mitochondrial DNA (mtDNA) deletions has been related to aging in many cell types of the body (Larsson, 2010). In skin, mtDNA deletions were mostly found in the dermis, but not in the epidermis, and especially in areas exposed to UV-irradiation (Berneburg et al., 2004; Krishnan et al., 2006). Epidermal turnover is fast due to continuously proliferating keratinocytes, in contrast to dermal fibroblasts that rarely divide. We hypothesize that the proliferation rate is key for variable accumulation of mtDNA deletions in different tissues. Understanding these processes in skin will help us to understand the contribution of mtDNA defects to aging in general and will allow us to test interventions in this easily accessible organ.
Our group has generated a mouse model that allows the expression of a mutated form of the mitochondrial helicase Twinkle (K320E point mutation) in the tissue of our choice.
We investigated the effect of K320E-Twinkle in slowly- or non-dividing cells such as dermal fibroblasts, skeletal muscle fibers and cardiomyocytes. Our results indicate that indeed the two latter models resemble human aging with accumulation of mtDNA deletions and consecutive late aging phenotypes like muscle fiber replacement (Kimoloi et al., submitted) and severe arrhythmia, respectively (Fig. 1. Baris et al., 2015). Dermal fibroblasts present mtDNA depletion when proliferating in vitro and mtDNA deletions, but no obvious aging phenotype in vivo (collaboration with AG Eming; Knuever, Boix et al., in preparation).
When expressing K320E-Twinkle in chondrocytes of the bone growth plate, mice developed a short stature, similar to many patients suffering from mitochondrial disease due to mtDNA mutations, and later showed cartilage degeneration typical for advanced age (Holzer et al., 2019).
In contrast, in the highly proliferative epidermis, the K320E-Twinkleepi keratinocytes show drastic mtDNA depletion instead of an accumulation of mtDNA deletions in vivo. This, however, does not lead to a severe epidermal phenotype but, surprisingly, to the early death of the mice with low levels of glucose and high lactate levels in blood and a severe inflammatory phenotype (Fig. 2. Weiland et al., 2018).
Those results, together with the fact that mtDNA deletions were not found in human UV-exposed epidermis, suggest that keratinocytes are protected from the accumulation of these mtDNA defects. The high epidermal proliferation rate may be key to prevent their accumulation. However, the unsolved question is: What are the molecular mechanisms that allow keratinocytes to escape from the accumulation of mtDNA defects?
Due to the early death of K320E-Twinkleepi mice we could not investigate the consequences of mtDNA deletions in the epidermis of adult mice and its contribution to skin aging and inflammation, which is now part of this new proposal.
Center of Physiology, Institute for Vegetative Physiology
Principal Investigator - C 17show more…
Institute for Vegetative Physiology
Co - Principal Investigator - C 17