Mitochondrial Complex I Dysfunction and Peripheral Chemoreflex Sensitivity in a FASTK-Deficient Mice Model
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.
KeywordsMitochondria Complex I. FASTK family proteins Carotid body chemoreceptors
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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