Mitochondrial function in murine skin epithelium is crucial for hair follicle morphogenesis and epithelial-mesenchymal interactions.
Here, we studied how epithelial energy metabolism impacts overall skin development by selectively deleting intraepithelial mtDNA in mice by ablating a key maintenance factor (Tfam(EKO)), which induces loss of function of the electron transport chain (ETC). Quantitative (immuno)histomorphometry demonstrated that Tfam(EKO) mice showed significantly reduced hair follicle (HF) density and morphogenesis, fewer intrafollicular keratin15+ epithelial progenitor cells, increased apoptosis, and reduced proliferation. Tfam(EKO) mice also displayed premature entry into (aborted) HF cycling by apoptosis-driven HF regression (catagen). Ultrastructurally, Tfam(EKO) mice exhibited severe HF dystrophy, pigmentary abnormalities, and telogen-like condensed dermal papillae. Epithelial HF progenitor cell differentiation (Plet1, Lrig1 Lef1, and β-catenin), sebaceous gland development (adipophilin, Scd1, and oil red), and key mediators/markers of epithelial-mesenchymal interactions during skin morphogenesis (NCAM, versican, and alkaline phosphatase) were all severely altered in Tfam(EKO) mice. Moreover, the number of mast cells, major histocompatibility complex class II+, or CD11b+ immunocytes in the skin mesenchyme was increased, and essentially no subcutis developed. Therefore, in contrast to their epidermal counterparts, pilosebaceous unit stem cells depend on a functional ETC. Most importantly, our findings point toward a frontier in skin biology: the coupling of HF keratinocyte mitochondrial function with the epithelial-mesenchymal interactions that drive overall development of the skin and its appendages.
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Jennifer E
JE
Kloepper
Institute for Vegetative Physiology, University of Köln, Köln, Germany.
Olivier R
OR
Baris
Center for Biochemistry, Medical Faculty at the University of Köln, Köln, Germany; Center for Molecular Medicine Köln, University of Köln, Köln, Germany.
Karen
K
Reuter
Laboratory of Dairy Food Science, Faculty of Agriculture, Hokkaido University, Sapporo, Japan.
Ken
K
Kobayashi
Institute for Vegetative Physiology, University of Köln, Köln, Germany.
Daniela
D
Weiland
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Silvia
S
Vidali
Centre for Skin Sciences, University of Bradford, Bradford, UK.
Desmond J
DJ
Tobin
Center for Biochemistry, Medical Faculty at the University of Köln, Köln, Germany; Center for Molecular Medicine Köln, University of Köln, Köln, Germany.
Catherin
C
Niemann
Institute for Vegetative Physiology, University of Köln, Köln, Germany; Center for Molecular Medicine Köln, University of Köln, Köln, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), Köln, Germany. Electronic address: rudolf.wiesner@uni-koeln.de.
Rudolf J
RJ
Wiesner
Department of Dermatology, University of Lübeck, Lübeck, Germany; Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
Ralf
R
Paus
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D018859:Hair Follicle / Q000166:cytology / Q000254:growth & development*; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D023421:Models, Animal; D009024:Morphogenesis / Q000502:physiology*; D012879:Skin Physiological Phenomena
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse