The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia

Publication date: Available online 7 April 2016
Source:Cell Reports
Author(s): Robert B. Hamanaka, Samuel E. Weinberg, Colleen R. Reczek, Navdeep S. Chandel
Hypoxia-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 abstract

Teaser

Hamanaka et al. show that loss of mitochondrial respiratory activity in the mouse epidermis impairs hypoxic activation of HIF-1. Since epidermal HIF-1 promotes cutaneous vasodilation and blood flow during hypoxia and potentiates the hypoxic response in the internal organs, mice with loss of TFAM in the epidermis are unable to induce renal erythropoietin expression in response to hypoxia.


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