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Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant

The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane...

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Autores principales: Senoo, Nanami, Chinthapalli, Dinesh K., Baile, Matthew G., Golla, Vinaya K., Saha, Bodhisattwa, Ogunbona, Oluwaseun B., Saba, James A., Munteanu, Teona, Valdez, Yllka, Whited, Kevin, Chorev, Dror, Alder, Nathan N., May, Eric R., Robinson, Carol V., Claypool, Steven M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187269/
https://www.ncbi.nlm.nih.gov/pubmed/37205478
http://dx.doi.org/10.1101/2023.05.05.539595
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author Senoo, Nanami
Chinthapalli, Dinesh K.
Baile, Matthew G.
Golla, Vinaya K.
Saha, Bodhisattwa
Ogunbona, Oluwaseun B.
Saba, James A.
Munteanu, Teona
Valdez, Yllka
Whited, Kevin
Chorev, Dror
Alder, Nathan N.
May, Eric R.
Robinson, Carol V.
Claypool, Steven M.
author_facet Senoo, Nanami
Chinthapalli, Dinesh K.
Baile, Matthew G.
Golla, Vinaya K.
Saha, Bodhisattwa
Ogunbona, Oluwaseun B.
Saba, James A.
Munteanu, Teona
Valdez, Yllka
Whited, Kevin
Chorev, Dror
Alder, Nathan N.
May, Eric R.
Robinson, Carol V.
Claypool, Steven M.
author_sort Senoo, Nanami
collection PubMed
description The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane and exchanges ADP and ATP to enable OXPHOS. Here, we investigated the role of these buried CLs in the carrier using yeast Aac2 as a model. We introduced negatively charged mutations into each CL-binding site of Aac2 to disrupt the CL interactions via electrostatic repulsion. While all mutations disturbing the CL-protein interaction destabilized Aac2 monomeric structure, transport activity was impaired in a pocket-specific manner. Finally, we determined that a disease-associated missense mutation in one CL-binding site in ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.
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spelling pubmed-101872692023-05-17 Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant Senoo, Nanami Chinthapalli, Dinesh K. Baile, Matthew G. Golla, Vinaya K. Saha, Bodhisattwa Ogunbona, Oluwaseun B. Saba, James A. Munteanu, Teona Valdez, Yllka Whited, Kevin Chorev, Dror Alder, Nathan N. May, Eric R. Robinson, Carol V. Claypool, Steven M. bioRxiv Article The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane and exchanges ADP and ATP to enable OXPHOS. Here, we investigated the role of these buried CLs in the carrier using yeast Aac2 as a model. We introduced negatively charged mutations into each CL-binding site of Aac2 to disrupt the CL interactions via electrostatic repulsion. While all mutations disturbing the CL-protein interaction destabilized Aac2 monomeric structure, transport activity was impaired in a pocket-specific manner. Finally, we determined that a disease-associated missense mutation in one CL-binding site in ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions. Cold Spring Harbor Laboratory 2023-05-06 /pmc/articles/PMC10187269/ /pubmed/37205478 http://dx.doi.org/10.1101/2023.05.05.539595 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Senoo, Nanami
Chinthapalli, Dinesh K.
Baile, Matthew G.
Golla, Vinaya K.
Saha, Bodhisattwa
Ogunbona, Oluwaseun B.
Saba, James A.
Munteanu, Teona
Valdez, Yllka
Whited, Kevin
Chorev, Dror
Alder, Nathan N.
May, Eric R.
Robinson, Carol V.
Claypool, Steven M.
Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant
title Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant
title_full Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant
title_fullStr Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant
title_full_unstemmed Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant
title_short Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant
title_sort conserved cardiolipin-mitochondrial adp/atp carrier interactions assume distinct structural and functional roles that are clinically relevant
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187269/
https://www.ncbi.nlm.nih.gov/pubmed/37205478
http://dx.doi.org/10.1101/2023.05.05.539595
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