Abstract
The molecular mechanisms underlying O2-sensing by carotid body (CB) chemoreceptors remain undetermined. Mitochondria have been implicated, due to the sensitivity of CB response to electron transport chain (ETC) blockers. ETC is one of the major sources of reactive oxygen species, proposed as mediators in oxygen sensing. Fas-activated serine/threonine phosphoprotein is a sensor of mitochondrial stress that modulates protein translation to promote survival of cells exposed to adverse conditions. A translational variant of Fas-activated serine/threonine kinase (FASTK) is required for the biogenesis of ND6 mRNA, the mitochondrial encoded subunit 6 of the NADH dehydrogenase complex (Complex I). Ablating FASTK expression reduced Complex I activity in vivo by about 50%. We have tested the hypothesis of Complex I participation in O2-sensing structures by studying the effect of hypoxia in FASTK−/− knockout mice. Ventilatory response to acute hypoxia and hypercapnia tests showed similar sensitivity and CB catecholaminergic activity in knockout and wild type mice; hypoxic pulmonary vasoconstriction response also was similar. Pulmonary artery contractility in vitro, using small vessel myography, showed a significantly decreased relaxation to rotenone in knockout mice pre-constricted vessels with PGF2α. In conclusion, FASTK−/− knockout mice maintain respiratory chemoreflex under hypoxia and hypercapnia stress suggesting that completely functional Complex I ND6 protein is not required for these responses.
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References
Archer SL, Huang J, Henry T, Peterson D, Weir EK (1993) A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 73(6):1100–1112
Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, Weir EK (1999) O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci U S A 96(14):7944–7949
Chen J, Gomez-Niño A, Gonzalez C, Dinger B, Fidone S (1997) Stimulus-specific mobilization of dopamine and norepinephrine stores in cat carotid body. J Auton Nerv Syst 67:109–113
Fernández-Agüera MC, Gao L, González-Rodríguez P, Pintado CO, Arias-Mayenco I, García-Flores P, García-Pergañeda A, Pascual A, Ortega-Sáenz P, López-Barneo J (2015) Oxygen sensing by arterial chemoreceptors depends on mitochondrial complex I signaling. Cell Metab 22(5):825–837
Gomez-Niño A, Agapito MT, Obeso A, Gonzalez C (2009) Effects of mitochondrial poisons on glutathione redox potential and carotidbody chemoreceptor activity. Respir Physiol Neurobiol 165:104–111
Gonzalez C, Almaraz L, Obeso A, Rigual R (1994) Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev 74(4):829–898
Gonzalez-Obeso E, Docio I, Olea E, Cogolludo A, Obeso A, Rocher A, Gomez-Niño A (2017) Guinea pig oxygen-sensing and carotid body functional properties. Front Physiol 8:285
Holmes AP, Turner PJ, Buckler KJ, Kumar P (2016) Moderate inhibition of mitochondrial function augments carotid body hypoxic sensitivity. Pflugers Arch 468(1):143–155
Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, Goldberger O, Peng J, Shalem O, Sanjana NE, Zhang F, Goessling W, Zapol WM, Mootha VK (2016) Hypoxia as a therapy for mitochondrial disease. Science 352(6281):54–61
Jourdain A, Koppen M, Rodley CD, Maundrell K, Gueguen N, Reynier P, Guaras AM, Enriquez JA, Anderson P, Simarro M, Martinou JC (2015) A mitochondria-specific isoform of FASTK is present in mitochondrial RNA granules and regulates gene expression and function. Cell Rep 10:1110–1121
López-Barneo J, López-López JR, Ureña J, González C (1988) Chemotransduction in the carotid body: K+ current modulated by PO2 in type I chemoreceptor cells. Science 241(4865):580–582
Post JM, Hume JR, Archer SL, Weir EK (1992) Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Phys 262(4 Pt 1):C882–C890
Rahman A, Ekman M, Shakirova Y, Andersson KE, Morgelin M, Erjefalt MJ, Brundin P, Li JL, Sward K (2013) Late onset vascular dysfunction in the R6/1 model of Huntington’s disease. Eur J Pharmacol 698:345–353
Richalet JP (1997) Oxygen sensors in the organism: examples of regulation under altitude hypoxia in mammals. Comp Biochem Physiol A Physiol 118(1):9–14
Simarro M, Giannattasio G, De la Fuente MA, Benarafa C, Subramanian KK, Ishizawar R, Balestrieri B, Andersson EM, Luo HR, Orduña A, Boyce J, Anderson P (2010) Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation. J Immunol 184(9):5325–5332
Acknowledgements
This work was supported by Grants BFU2015-63706R (MINECO, FEDER-UE) and CIBER CB06/06/0050 from ISCiii (Spain). The Authors thank R. Cantalapiedra and R. Carretero for technical assistance.
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Gomez-Niño, A., Docio, I., Prieto-Lloret, J., Simarro, M., de la Fuente, M.A., Rocher, A. (2018). Mitochondrial Complex I Dysfunction and Peripheral Chemoreflex Sensitivity in a FASTK-Deficient Mice Model. In: Gauda, E., Monteiro, M., Prabhakar, N., Wyatt, C., Schultz, H. (eds) Arterial Chemoreceptors. Advances in Experimental Medicine and Biology, vol 1071. Springer, Cham. https://doi.org/10.1007/978-3-319-91137-3_6
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