The [2Fe-2S] cluster of mitochondrial outer membrane protein mitoNEET has an O2-regulated nitric oxide access tunnel
Thao Nghi Hoang (Da Nang University of Medical Technology and Pharmacy, King’s College London)
Meritxell Wu-Lu (Technical University of Berlin)
Alberto Collauto (Imperial College London)
Peter Leon Hagedoorn (TU Delft - BT/Biocatalysis)
Madalina Alexandru (King’s College London)
Maike Henschel (King’s College London)
Shahram Kordasti (King’s College London)
Maria Andrea Mroginski (Technical University of Berlin)
Maxie M. Roessler (Imperial College London)
Kourosh H. Ebrahimi (King’s College London)
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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.
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