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Updated: Feb 3, 2026

An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
Mitochondrial Complex I Dysfunction and Peripheral Chemoreflex Sensitivity in a FASTK-Deficient Mice Model
Angela Gomez-Niño1,2, Inmaculada Docio3,4, Jesus Prieto-Lloret3,4
1Departamento de Biologia Celular, Histologia y Farmacologia/IBGM, Universidad de Valladolid-CSIC, Valladolid, Spain. angela@biocel.uva.es.
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.
Insights
Mitochondrial Complex I is not essential for oxygen sensing in carotid bodies. Studies in FASTK knockout mice show normal respiratory responses to hypoxia, indicating Complex I
Area of Science:
- Cellular Physiology
- Mitochondrial Biology
- Respiratory Control
Background:
- The precise molecular mechanisms of oxygen sensing by carotid body (CB) chemoreceptors are not fully understood.
- Mitochondria, particularly the electron transport chain (ETC), are implicated in CB oxygen sensing due to sensitivity to ETC blockers.
- Reactive oxygen species (ROS) generated by the ETC are proposed mediators of oxygen sensing.
Purpose of the Study:
- To investigate the role of mitochondrial Complex I in oxygen sensing by the carotid body.
- To test the hypothesis that Complex I is essential for O2-sensing structures.
- To study the effects of hypoxia on FASTK knockout mice, which have impaired Complex I biogenesis.
Main Methods:
- Generation and study of FASTK knockout (FASTK-/-) mice with reduced Complex I activity.
- Assessment of ventilatory responses to acute hypoxia and hypercapnia.
- Measurement of carotid body catecholaminergic activity and hypoxic pulmonary vasoconstriction.
- In vitro pulmonary artery contractility studies using small vessel myography.
Main Results:
- FASTK knockout mice exhibited normal ventilatory sensitivity to hypoxia and hypercapnia compared to wild-type mice.
- Carotid body catecholaminergic activity and hypoxic pulmonary vasoconstriction responses were similar in both groups.
- Pulmonary artery vessels from knockout mice showed reduced relaxation to rotenone, an Complex I inhibitor.
Conclusions:
- Complete functional Complex I, specifically the ND6 subunit, is not required for respiratory chemoreflex under hypoxic and hypercapnic conditions.
- The study suggests alternative pathways or compensatory mechanisms are involved in carotid body oxygen sensing.
- While Complex I function is affected, its complete absence does not abolish critical oxygen-sensing responses.
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