The Mitochondrial Electron Transport Chain Is Dispensable for Proliferation and Differentiation of Epidermal Progenitor Cells

Abstract

Tissue stem cells and germ line or embryonic stem cells were shown to have reduced oxidative metabolism, which was proposed to be an adaptive mechanism to reduce damage accumulation caused by reactive oxygen species. However, an alternate explanation is that stem cells are less dependent on specialized cytoplasmic functions compared with differentiated cells, therefore, having a high nuclear-to-cytoplasmic volume ratio and consequently a low mitochondrial content. To determine whether stem cells rely or not on mitochondrial respiration, we selectively ablated the electron transport chain in the basal layer of the epidermis, which includes the epidermal progenitor/stem cells (EPSCs). This was achieved using a loxP-flanked mitochondrial transcription factor A (Tfam) allele in conjunction with a keratin 14 Cre transgene. The epidermis of these animals (Tfam EKO ) showed a profound depletion of mitochondrial DNA and complete absence of respiratory chain complexes. However, despite a short lifespan due to malnutrition, epidermal development and skin barrier function were not impaired. Differentiation of epidermal layers was normal and no proliferation defect or major increase of apoptosis could be observed. In contrast, mice with an epidermal ablation of prohibitin-2, a scaffold protein in the inner mitochondrial membrane, displayed a dramatic phenotype observable already in utero, with severely impaired skin architecture and barrier function, ultimately causing death from dehydration shortly after birth. In conclusion, we here provide unequivocal evidence that EPSCs, and probably tissue stem cells in general, are independent of the mitochondrial respiratory chain, but still require a functional dynamic mitochondrial compartment.

Mitochondrial Reactive Oxygen Species Promote Epidermal Differentiation and Hair Follicle Development

“…1E). Although the TFAM fl/fl mice used in both studies are on a C57BL/6 background, the backgrounds of the KRT14-Cre mice differ [B6CBAF1 in the present study, C57BL/6 in (47)], which could contribute to the observed life span differences.…”

“…Baris and colleagues have also generated mice lacking TFAM in the epidermis (47), which die within the first week after birth. Although they show reduced abundance of loricrin and keratin 10 in the epidermis of their mice, Baris and colleagues conclude that epidermal differentiation occurs normally in TFAM cKO mice.…”

Quantitative proteomic analysis of sphere-forming stem-like oral cancer cells

“…PHB2 acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases. Recent studies have demonstrated that epidermal stem cells are highly dependent on PHB2 for maintaining mitochondrial function [35]. Nuclear lamins are fibrous proteins which interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelope.…”

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

“…in organ-cultured human skin under serum-and TH-free conditions. First, we investigated the expression of mitochondrially encoded cytochrome c oxidase I (MTCO1), the mitochondrial transcription factor A (TFAM), which controls mitochondrial biogenesis and mitochondrial DNA synthesis (Baris et al, 2011;Campbell et al, 2012;Kloepper et al, 2015;Shutt et al, 2011), and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), a key transcription factor that regulates mitochondrial biogenesis and numerous other cell functions including aging, whose reduction in activity has an aging-promoting effect (Dabrowska et al, 2015;Gilbert, 2013;Riera and Dillin, 2015). To assess whether any expression changes in these parameters altered also the intraepidermal mitochondrial oxidative phosphorylation, we asked whether THs modified the activity of complex I, the initial step of the mitochondrial respiratory chain (Chandel and Jeffs, 2015;Hirst, 2013;Scheffler, 2008).…”