The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia

• The respiratory chain is essential for hypoxic activation of HIF in keratinocytes
• Respiratory chain production of ROS is necessary for hypoxic activation of HIF in vitro
• Hypoxic activation of HIF in the epidermis requires the respiratory chain in vivo
• Epidermal respiration is essential for hypoxic expression of renal erythropoietin gene

SummaryHypoxia-inducible factors (HIFs) are crucial for cellular and organismal adaptation to hypoxia. The mitochondrial respiratory chain is the largest consumer of oxygen in most mammalian cells; however, it is unknown whether the respiratory chain is necessary for in vivo activation of HIFs and organismal adaptation to hypoxia. HIF-1 activation in the epidermis has been shown to be a key regulator of the organismal response to hypoxic conditions, including renal production of erythropoietin (Epo). Therefore, we conditionally deleted expression of TFAM in mouse epidermal keratinocytes. TFAM is required for maintenance of the mitochondrial genome, and TFAM-null cells are respiratory deficient. TFAM loss in epidermal keratinocytes reduced epidermal levels of HIF-1α protein and diminished the hypoxic induction of HIF-dependent transcription in epidermis. Furthermore, epidermal TFAM deficiency impaired hypoxic induction of renal Epo expression. Our results demonstrate that the mitochondrial respiratory chain is essential for in vivo HIF activation and organismal adaptation to hypoxia.

Graphical AbstractFigure optionsDownload as PowerPoint slide