The epidermis is the first line of protection against external microbial, chemical, and thermal insults. The epidermis also protects us from excessive fluid loss, preventing dehydration. In order to maintain its protective function, epidermis and its appendages the hair follicles (HF) and sebaceous glands (SG) undergo continual homeostatic renewal. In addition to its barrier function, epidermis has been recently reported to be an integral part of the organismal oxygen sensing machinery. Mitochondrial dysfunction can manifest in hair and skin disorders. Moreover, aging is associated with an increase in mutations within mitochondrial DNA that leads to mitochondrial dysfunction. Genetically engineered mice with mutations in mitochondria DNA show an accelerated aging phenotype that includes hair loss. Previous reports suggest that mitochondrial dysfunction leads to high production of reactive oxygen species (ROS) leading to oxidative damage of DNA and other cellular components and resulting in cell death. However, we have published extensively on demonstrating that mitochondrial ROS serve as signaling molecules regulating hypoxia-induced gene expression and oncogene-induced tumor cell proliferation. Thus, we favor the idea that if mitochondrial dysfunction results in a decrease in mitochondrial ROS generation then ROS mediated signaling that is necessary for cells to maintain homeostasis and adapt to stress is disabled. Based on our previous data, we will test the hypothesis that mitochondrial generation of ROS is required for epidermal homeostasis and function by allowing for the proper differentiation. We have developed two conditional knockout mouse models which will allow us to induce mitochondrial dysfunction in the epidermis while either maintaining or eliminating ROS production from the mitochondria.
This grant will test whether mitochondria ROS serve as positive signaling molecules regulating hair and skin homeostasis.
| Hamanaka, Robert B; Weinberg, Samuel E; Reczek, Colleen R et al. (2016) The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia. Cell Rep 15:451-459 |
| Hamanaka, Robert B; Glasauer, Andrea; Hoover, Paul et al. (2013) Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci Signal 6:ra8 |
