The cellular response to hypoxia is governed largely by a family of transcription factors termed hypoxia-inducible factors (HIFs), which promote the activation of genes involved in glycolysis, angiogenesis, cell-cycle regulation, and survival.
Mitochondrial generation of tricarboxylic acid (TCA) cycle intermediates, consumption of oxygen, and production of reactive oxygen species (ROS) have been shown to inhibit the hydroxylation of HIFs, resulting in activation of HIF target genes. Despite evidence for the role of mitochondrial metabolism in regulating the cellular response to hypoxia, it remains to be demonstrated whether this phenomenon, heretofore observed only in cell culture, plays a physiological role in the mammalian systemic response to hypoxia in vivo.
Epidermal keratinocytes have been shown to play a critical role in regulating the systemic response to hypoxia. The epidermis, which obtains oxygen directly from the atmosphere, responds to reductions in atmospheric oxygen by inducing vasodilation in the underlying dermis in a HIF- and nitric-oxide-dependent manner. This hypoxic vasodilation in the skin results in reduced blood flow to the internal organs, increasing internal hypoxia and promoting renal production of erythropoietin (Epo), a glycoprotein hormone that promotes proliferation and differentiation of erythroid progenitor cells into red blood cells, increasing the oxygen carrying capacity of the blood.
The team recently reported on mice that lack expression of transcription factor A, mitochondrial (TFAM) in epidermal keratinocytes. TFAM is required for transcription and replication of the mitochondrial genome, and cells lacking TFAM are respiratory deficient. Loss of TFAM in epidermal keratinocytes resulted in epidermal barrier function defects and lethality 2 weeks after birth. The epidermal defect was due to a decrease in the production of mitochondrial ROS, which is necessary for Notch-dependent epidermal differentiation.
In this study the team shows that epidermal keratinocytes derived from these TFAM epidermal knockout (TFAM EpiKO) mice display impaired HIF activation upon exposure to hypoxia. Furthermore, neonatal mice displayed diminished HIF-1α protein and target gene induction in their epidermis after exposure to hypoxia. This resulted in an impaired hypoxic induction of Epo expression in the kidneys of these mice.
Renal Epo expression could be induced in TFAM EpiKO mice by pharmacologic promotion of cutaneous vasodilation or by co-deletion of VHL, demonstrating conclusively the link between mitochondria and the HIF degradation machinery in vivo. Our results demonstrate that the mitochondrial respiratory chain is essential for in vivo HIF activation and organismal adaptation to hypoxia.