Mitochondrial Complex I Dysfunction and Peripheral Chemoreflex Sensitivity in a FASTK-Deficient Mice Model

Gomez-Niño, Angela; Docio, Inmaculada; Prieto‐Lloret, Jesus; Simarro, Marı́a; Fuente, Miguel A. de la; Rocher, A.

doi:10.1007/978-3-319-91137-3_6

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…FASTK is recently identified as a RNA-binding protein to promote MTND6 mRNA maturation (Jourdain et al, 2015). Genetic ablation of FASTK causes a marked reduction of complex I activity in mammalian cells, highlighting FASTK is essential to maintain normal complex I function (García Del Río et al, 2018;Gomez-Niño et al, 2018). The present study shows that the FASTK deficient heart is highly susceptible to I/R-induced complex I dysfunction and respiration, confirming that FASTK critically modulates myocardial mitochondrial complex I activity even under stressful conditions such as I/R.…”

Section: Discussionsupporting

confidence: 72%

“…In mammalian cells, FASTK specifically interacts with the mRNA of NADH dehydrogenase subunit 6 (MTND6, a mitochondrial gene encoding a subunit of complex I) at various sites and is essential for the processing and maturation of MTND6 mRNA (Jourdain et al, 2015). In vivo and in vitro studies have confirmed that genetic ablation of FASTK decreased the expression of MTND6 and thereafter suppressed mitochondrial complex I activity approximately by 50% (García Del Río et al, 2018;Gomez-Niño et al, 2018). These data reveal that FASTK is a novel and important modulator of mitochondrial complex I activity and respiratory function.…”

Section: Introductionmentioning

confidence: 99%

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Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Chen

Wang

et al. 2021

Front. Cell Dev. Biol.

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Cardiac energy homeostasis is strictly controlled by the mitochondrial complex-mediated respiration. In the heart, mitochondrial complex I is highly susceptible to functional and structural destroy after ischemia/reperfusion (I/R), thereby contributing to myocardial energy insufficiency and cardiomyocyte death. Fas-activated serine/threonine kinase (FASTK) is recently recognized as a key modulator of mitochondrial gene expression and respiration. However, the role of FASTK in cardiac I/R process is undetermined. Here, we show that FASTK expression was down-regulated in the post-I/R heart. The reactive oxygen species scavenger N-acetyl-L-cysteine reversed I/R-induced FASTK down-regulation. Genetic deletion of FASTK exacerbated I/R-induced cardiac dysfunction, enlarged myocardial infarct size, and increased cardiomyocyte apoptosis. Compared with the wild type control, the FASTK deficient heart exhibited a lower mRNA expression of NADH dehydrogenase subunit-6 (MTND6, a mitochondrial gene encoding a subunit of complex I) and was more vulnerable to I/R-associated complex I inactivation. Replenishment of FASTK expression via adenovirus-mediated gene delivery restored mitochondrial complex I activity and ameliorated cardiomyocyte death induced by I/R, whereas these beneficial effects were blocked by the co-treatment with rotenone, a specific complex I inhibitor. in vivo experiments further confirmed that cardiac overexpression of FASTK ameliorated I/R-related MTND6 down-regulation and mitochondrial complex I inactivation, thereby protecting the heart against I/R injury. Collectively, these data for the first time identify that the down-regulation of FASTK is a direct culprit behind the loss of mitochondrial complex I functional integrity and cardiac injury induced by I/R process. Targeting FASTK might be a promising and effective strategy for MI/R intervention.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Chen

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…These cells did, however, respond to hypercapnia, confirming functionality and selective depletion in O 2 sensing capabilities. The Ndufs2 gene appears to be of particular importance as genetic deletion of Mt-nd6 , (the mitochondrial encoded subunit six of the NADH dehydrogenase complex), did not impair CB or ventilatory responses to hypoxia ( Gomez-Nino et al, 2018 ). Intracellular delivery of exogenous H 2 O 2 has been shown to increase input resistance, indicative of an inhibitory action on leak K + channels ( Fernandez-Aguera et al, 2015 ).…”

Section: Are Mitochondrial Ros and Changes In Nad + ...mentioning

confidence: 99%

Are Multiple Mitochondrial Related Signalling Pathways Involved in Carotid Body Oxygen Sensing?

et al. 2022

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It is generally acknowledged that the carotid body (CB) type I cell mitochondria are unique, being inhibited by relatively small falls in PaO2 well above those known to inhibit electron transport in other cell types. This feature is suggested to allow for the CB to function as an acute O2 sensor, being stimulated and activating systemic protective reflexes before the metabolism of other cells becomes compromised. What is less clear is precisely how a fall in mitochondrial activity links to type I cell depolarisation, a process that is required for initiation of the chemotransduction cascade and post-synaptic action potential generation. Multiple mitochondrial/metabolic signalling mechanisms have been proposed including local generation of mitochondrial reactive oxygen species (mitoROS), a change in mitochondrial/cellular redox status, a fall in MgATP and an increase in lactate. Although each mechanism is based on compelling experimental evidence, they are all not without question. The current review aims to explore the importance of each of these signalling pathways in mediating the overall CB response to hypoxia. We suggest that there is unlikely to be a single mechanism, but instead multiple mitochondrial related signalling pathways are recruited at different PaO2s during hypoxia. Furthermore, it still remains to be determined if mitochondrial signalling acts independently or in partnership with extra-mitochondrial O2-sensors.

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Prognostic significance of the Cdk5 gene in breast cancer: an in silico study

Lisany¹,

Jamal

Chung

et al. 2020

Netw Model Anal Health Inform Bioinforma

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Mitochondrial Complex I Dysfunction and Peripheral Chemoreflex Sensitivity in a FASTK-Deficient Mice Model

Cited by 5 publications

References 15 publications

Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Are Multiple Mitochondrial Related Signalling Pathways Involved in Carotid Body Oxygen Sensing?

Prognostic significance of the Cdk5 gene in breast cancer: an in silico study

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