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NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate

Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional cons...

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Autores principales: D’Angelo, Luigi, Astro, Elisa, De Luise, Monica, Kurelac, Ivana, Umesh-Ganesh, Nikkitha, Ding, Shujing, Fearnley, Ian M., Gasparre, Giuseppe, Zeviani, Massimo, Porcelli, Anna Maria, Fernandez-Vizarra, Erika, Iommarini, Luisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076766/
https://www.ncbi.nlm.nih.gov/pubmed/33882309
http://dx.doi.org/10.1016/j.celrep.2021.109002
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author D’Angelo, Luigi
Astro, Elisa
De Luise, Monica
Kurelac, Ivana
Umesh-Ganesh, Nikkitha
Ding, Shujing
Fearnley, Ian M.
Gasparre, Giuseppe
Zeviani, Massimo
Porcelli, Anna Maria
Fernandez-Vizarra, Erika
Iommarini, Luisa
author_facet D’Angelo, Luigi
Astro, Elisa
De Luise, Monica
Kurelac, Ivana
Umesh-Ganesh, Nikkitha
Ding, Shujing
Fearnley, Ian M.
Gasparre, Giuseppe
Zeviani, Massimo
Porcelli, Anna Maria
Fernandez-Vizarra, Erika
Iommarini, Luisa
author_sort D’Angelo, Luigi
collection PubMed
description Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we determine the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover the function of TMEM126A, the product of a disease gene causing recessive optic atrophy as a factor necessary for the correct assembly and function of CI.
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spelling pubmed-80767662021-04-29 NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate D’Angelo, Luigi Astro, Elisa De Luise, Monica Kurelac, Ivana Umesh-Ganesh, Nikkitha Ding, Shujing Fearnley, Ian M. Gasparre, Giuseppe Zeviani, Massimo Porcelli, Anna Maria Fernandez-Vizarra, Erika Iommarini, Luisa Cell Rep Article Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we determine the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover the function of TMEM126A, the product of a disease gene causing recessive optic atrophy as a factor necessary for the correct assembly and function of CI. Cell Press 2021-04-21 /pmc/articles/PMC8076766/ /pubmed/33882309 http://dx.doi.org/10.1016/j.celrep.2021.109002 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
D’Angelo, Luigi
Astro, Elisa
De Luise, Monica
Kurelac, Ivana
Umesh-Ganesh, Nikkitha
Ding, Shujing
Fearnley, Ian M.
Gasparre, Giuseppe
Zeviani, Massimo
Porcelli, Anna Maria
Fernandez-Vizarra, Erika
Iommarini, Luisa
NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
title NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
title_full NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
title_fullStr NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
title_full_unstemmed NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
title_short NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate
title_sort ndufs3 depletion permits complex i maturation and reveals tmem126a/opa7 as an assembly factor binding the nd4-module intermediate
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076766/
https://www.ncbi.nlm.nih.gov/pubmed/33882309
http://dx.doi.org/10.1016/j.celrep.2021.109002
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