Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling

• Published in: Cell metabolism Vol. 22; no. 5; pp. 825 - 837
• Main Authors: Fernández-Agüera, M. Carmen, Gao, Lin, González-Rodríguez, Patricia, Pintado, C. Oscar, Arias-Mayenco, Ignacio, García-Flores, Paula, García-Pergañeda, Antonio, Pascual, Alberto, Ortega-Sáenz, Patricia, López-Barneo, José
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2015
• Subjects: Adenosine Triphosphate - metabolism; Animals; Carotid Body - cytology; Carotid Body - metabolism; Cell Hypoxia; Chemoreceptor Cells - metabolism; Electron Transport Complex I - metabolism; Homeostasis; Mice; Mice, Knockout; Mitochondria - metabolism; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Oxygen - metabolism; Potassium Channels - metabolism; Signal Transduction
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.09.004

O2 sensing is essential for mammalian homeostasis. Peripheral chemoreceptors such as the carotid body (CB) contain cells with O2-sensitive K+ channels, which are inhibited by hypoxia to trigger fast adaptive cardiorespiratory reflexes. How variations of O2 tension (PO2) are detected and the mechanisms whereby these changes are conveyed to membrane ion channels have remained elusive. We have studied acute O2 sensing in conditional knockout mice lacking mitochondrial complex I (MCI) genes. We inactivated Ndufs2, which encodes a protein that participates in ubiquinone binding. Ndufs2-null mice lose the hyperventilatory response to hypoxia, although they respond to hypercapnia. Ndufs2-deficient CB cells have normal functions and ATP content but are insensitive to changes in PO2. Our data suggest that chemoreceptor cells have a specialized succinate-dependent metabolism that induces an MCI state during hypoxia, characterized by the production of reactive oxygen species and accumulation of reduced pyridine nucleotides, which signal neighboring K+ channels. [Display omitted] •Acute O2 sensing by peripheral chemoreceptors requires mitochondrial complex I function•O2-sensitive carotid body glomus cells can resist complex I dysfunction•Glomus cells have a specialized succinate-dependent metabolism•Reactive oxygen species and pyridine nucleotides signal K+ channels during hypoxia Oxygen sensing by carotid body cells is essential for homeostasis. Fernández-Agüera et al. show that responsiveness of chemoreceptor cells to hypoxia is selectively abolished by mutations in mitochondrial complex I disrupting the ubiquinone-binding site. Under hypoxia, complex I-derived reactive oxygen species and reduced pyridine nucleotides inhibit membrane K+ channels to induce cell activation.