Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 591, Issue 14, Pages 3549-3563Publisher
WILEY
DOI: 10.1113/jphysiol.2013.257741
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Funding
- Medical Research Council Project UK [G101134]
- Medical Research Council [G1001134] Funding Source: researchfish
- MRC [G1001134] Funding Source: UKRI
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The mechanism of oxygen sensing in arterial chemoreceptors is unknown but has often been linked to mitochondrial function. A common criticism of this hypothesis is that mitochondrial function is insensitive to physiological levels of hypoxia. Here we investigate the effects of hypoxia (down to 0.5% O-2) on mitochondrial function in neonatal rat type-1 cells. The oxygen sensitivity of mitochondrial [NADH] was assessed by monitoring autofluorescence and increased in hypoxia with a P-50 of 15 mm Hg (1 mm Hg = 133.3 Pa) in normal Tyrode or 46 mm Hg in Ca2+-free Tyrode. Hypoxia also depolarised mitochondrial membrane potential ((m), measured using rhodamine 123) with a P-50 of 3.1, 3.3 and 2.8 mm Hg in normal Tyrode, Ca2+-free Tyrode and Tyrode containing the Ca2+ channel antagonist Ni2+, respectively. In the presence of oligomycin and low carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP; 75 nm) (m) is maintained by electron transport working against an artificial proton leak. Under these conditions hypoxia depolarised (m)/inhibited electron transport with a P-50 of 5.4 mm Hg. The effects of hypoxia upon cytochrome oxidase activity were investigated using rotenone, myxothiazol, antimycin A, oligomycin, ascorbate and the electron donor tetramethyl-p-phenylenediamine. Under these conditions (m) is maintained by complex IV activity alone. Hypoxia inhibited cytochrome oxidase activity (depolarised (m)) with a P-50 of 2.6 mm Hg. In contrast hypoxia had little or no effect upon NADH (P-50= 0.3 mm Hg), electron transport or cytochrome oxidase activity in sympathetic neurons. In summary, type-1 cell mitochondria display extraordinary oxygen sensitivity commensurate with a role in oxygen sensing. The reasons for this highly unusual behaviour are as yet unexplained.
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