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Review
. 2010 Dec 31;174(3):175-81.
doi: 10.1016/j.resp.2010.08.004. Epub 2010 Aug 11.

Mitochondrial complex III: an essential component of universal oxygen sensing machinery?

Navdeep S Chandel  1
Affiliations
Review

Mitochondrial complex III: an essential component of universal oxygen sensing machinery?

Navdeep S Chandel. Respir Physiol Neurobiol. .

Abstract

Oxygen is necessary for the survival of mammalian cells. In order to maintain adequate cellular oxygenation, mammals have evolved multiple acute and long-term adaptive responses to hypoxia. These include hypoxic increases in erythropoiesis, pulmonary vasoconstriction and carotid body neurosecretion. Collectively, these responses help maintain oxygen homeostasis as oxygen levels remain scarce. There are multiple effectors proposed to underlie these diverse responses to hypoxia including PHD2, AMPK, NADPH oxidases, and mitochondrial complex III. Here I propose a model wherein complex III is integral to oxygen sensing in regulating diverse response to hypoxia.

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Figures

Figure 1
Figure 1. Oxygen sensing mechanisms during acute and prolonged hypoxia
Acute oxygen sensing is important for hypoxic pulmonary vasoconstriction (HPV) and hypoxic neurosecretion by the carotid body (CB). These two responses are dependent on an increase in intracellular calcium. Mitochondrial complex III generated ROS are critical for increased intracellular calcium levels which trigger HPV. This signal is amplified by activation of NOX family members. AMPK is also important for the rise in calcium during HPV. However, it is not clear whether an increase in mitochondrial ROS or AMP/ATP ratio is critical for AMPK activation during hypoxia. Presently, the role of mitochondrial ROS or NOX family members is not clarified for CB neurosecretion during hypoxia. However, there is data to support that AMPK activation is necessary for CB neurosecretion during hypoxia. The prolonged response to hypoxia triggers the activation of the transcription factor HIFs which are composed of two subunits, an oxygen sensitive HIF-α and HIF-β. HIF-α is hydroxylated at two different proline residues under normoxia by PHD2. The hydroxylation of proline residues serves as a recognition motif for pVHL. The binding of pVHL targets the HIF-α protein for ubiquitin mediated degradation. Under hypoxia, the hydroxylation of proline is diminished, which allows for the protein to be stabilized and bind to HIF-1β as well as p300/CBP to allow HIF dependent transcription of genes such as EPO which increases red blood cell proliferation and maturation to increase oxygen carry capacity in blood. Present data suggests that hypoxia increases mitochondrial complex III ROS production, diminishing the hydroxylation of the HIF-α protein. NOX family members are also transcriptionally induced by HIF-1, further amplifying the ROS signal.
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