The [2Fe-2S] cluster of mitochondrial outer membrane protein mitoNEET has an O2-regulated nitric oxide access tunnel

Thao Nghi Hoang; Meritxell Wu-Lu; Alberto Collauto; Peter-Leon Hagedoorn; Madalina Alexandru; Maike Henschel; Shahram Kordasti; Maria Andrea Mroginski; Maxie M Roessler; Kourosh H Ebrahimi

doi:10.1002/1873-3468.15097

The [2Fe-2S] cluster of mitochondrial outer membrane protein mitoNEET has an O₂-regulated nitric oxide access tunnel

Thao Nghi Hoang
, Meritxell Wu-Lu
, Alberto Collauto
, Peter-Leon Hagedoorn
, Madalina Alexandru
, Maike Henschel
, Shahram Kordasti
, Maria Andrea Mroginski
, Maxie M Roessler
, Kourosh H Ebrahimi

Technical University of Berlin
Imperial College London
Delft University of Technology

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

49 Downloads (Pure)

Abstract

The mitochondrial outer membrane iron-sulphur ([Fe-S]) protein mitoNEET has been extensively studied as a target of the anti-inflammatory and type-2 diabetes drug pioglitazone and as a protein affecting mitochondrial respiratory rate. Despite these extensive past studies, its molecular function has yet to be discovered. Here, we applied an interdisciplinary approach and discovered an explicit nitric oxide (NO) access site to the mitoNEET [2Fe-2S] cluster. We found that O₂ and pioglitazone block NO access to the cluster, suggesting a molecular function for the mitoNEET [2Fe-2S] cluster in mitochondrial signal transduction. Our discovery hints at a new pathway via which mitochondria can sense hypoxia through O₂ protection of the mitoNEET [2Fe-2S] cluster, a new paradigm in understanding the importance of [Fe-S] clusters for gasotransmitter signal transduction in eukaryotes.

Original language	English
Pages (from-to)	952-970
Number of pages	19
Journal	FEBS Letters
Volume	599
Issue number	7
Early online date	5 Jan 2025
DOIs	https://doi.org/10.1002/1873-3468.15097
Publication status	Published - Apr 2025

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Nitric Oxide/metabolism
Iron-Sulfur Proteins/metabolism
Oxygen/metabolism
Mitochondrial Proteins/metabolism
Humans
Mitochondrial Membranes/metabolism
Pioglitazone
Mitochondria/metabolism
Signal Transduction

Access to Document

10.1002/1873-3468.15097Licence: CC BY

The 2Fe‐2S cluster of_HOANG_Publishedonline5January2025_GOLD_VoR (CC BY)Final published version, 2.2 MBLicence: CC BY

Cite this

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title = "The [2Fe-2S] cluster of mitochondrial outer membrane protein mitoNEET has an O2-regulated nitric oxide access tunnel",

abstract = "The mitochondrial outer membrane iron-sulphur ([Fe-S]) protein mitoNEET has been extensively studied as a target of the anti-inflammatory and type-2 diabetes drug pioglitazone and as a protein affecting mitochondrial respiratory rate. Despite these extensive past studies, its molecular function has yet to be discovered. Here, we applied an interdisciplinary approach and discovered an explicit nitric oxide (NO) access site to the mitoNEET [2Fe-2S] cluster. We found that O2 and pioglitazone block NO access to the cluster, suggesting a molecular function for the mitoNEET [2Fe-2S] cluster in mitochondrial signal transduction. Our discovery hints at a new pathway via which mitochondria can sense hypoxia through O2 protection of the mitoNEET [2Fe-2S] cluster, a new paradigm in understanding the importance of [Fe-S] clusters for gasotransmitter signal transduction in eukaryotes. ",

keywords = "Nitric Oxide/metabolism, Iron-Sulfur Proteins/metabolism, Oxygen/metabolism, Mitochondrial Proteins/metabolism, Humans, Mitochondrial Membranes/metabolism, Pioglitazone, Mitochondria/metabolism, Signal Transduction",

author = "Hoang, \{Thao Nghi\} and Meritxell Wu-Lu and Alberto Collauto and Peter-Leon Hagedoorn and Madalina Alexandru and Maike Henschel and Shahram Kordasti and Mroginski, \{Maria Andrea\} and Roessler, \{Maxie M\} and Ebrahimi, \{Kourosh H\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). FEBS Letters published by John Wiley \& Sons Ltd on behalf of Federation of European Biochemical Societies.",

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doi = "10.1002/1873-3468.15097",

language = "English",

volume = "599",

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AU - Hoang, Thao Nghi

AU - Wu-Lu, Meritxell

AU - Collauto, Alberto

AU - Hagedoorn, Peter-Leon

AU - Alexandru, Madalina

AU - Henschel, Maike

AU - Kordasti, Shahram

AU - Mroginski, Maria Andrea

AU - Roessler, Maxie M

AU - Ebrahimi, Kourosh H

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N2 - The mitochondrial outer membrane iron-sulphur ([Fe-S]) protein mitoNEET has been extensively studied as a target of the anti-inflammatory and type-2 diabetes drug pioglitazone and as a protein affecting mitochondrial respiratory rate. Despite these extensive past studies, its molecular function has yet to be discovered. Here, we applied an interdisciplinary approach and discovered an explicit nitric oxide (NO) access site to the mitoNEET [2Fe-2S] cluster. We found that O2 and pioglitazone block NO access to the cluster, suggesting a molecular function for the mitoNEET [2Fe-2S] cluster in mitochondrial signal transduction. Our discovery hints at a new pathway via which mitochondria can sense hypoxia through O2 protection of the mitoNEET [2Fe-2S] cluster, a new paradigm in understanding the importance of [Fe-S] clusters for gasotransmitter signal transduction in eukaryotes.

AB - The mitochondrial outer membrane iron-sulphur ([Fe-S]) protein mitoNEET has been extensively studied as a target of the anti-inflammatory and type-2 diabetes drug pioglitazone and as a protein affecting mitochondrial respiratory rate. Despite these extensive past studies, its molecular function has yet to be discovered. Here, we applied an interdisciplinary approach and discovered an explicit nitric oxide (NO) access site to the mitoNEET [2Fe-2S] cluster. We found that O2 and pioglitazone block NO access to the cluster, suggesting a molecular function for the mitoNEET [2Fe-2S] cluster in mitochondrial signal transduction. Our discovery hints at a new pathway via which mitochondria can sense hypoxia through O2 protection of the mitoNEET [2Fe-2S] cluster, a new paradigm in understanding the importance of [Fe-S] clusters for gasotransmitter signal transduction in eukaryotes.

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KW - Iron-Sulfur Proteins/metabolism

KW - Oxygen/metabolism

KW - Mitochondrial Proteins/metabolism

KW - Humans

KW - Mitochondrial Membranes/metabolism

KW - Pioglitazone

KW - Mitochondria/metabolism

KW - Signal Transduction

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