Poster Presentation 21st International Conference on Biological Inorganic Chemistry 2025

DISCOVERING AN O2-REGULATED NITRIC OXIDE TUNNEL OF [2Fe-2S] CLUSTER OF TYPE-2 DIABETIC DRUG TARGET MITONEET (#400)

Thao Nghi Hoang 1 2 , Meritxell Wu-Lu 3 , Alberto Collauto 4 , Peter-Leon Hagedoorn 5 , Madalina Alexandru 1 6 , Maike Henschel 1 6 , Shahram Kordasti 6 , Maria Andrea Mroginski 3 , Maxie M. Roessler 4 , Kourosh Ebrahimi 1
  1. Institute of Pharmaceutical Science, King’s College London, London, United Kingdom
  2. Department of Pharmacy, Da Nang University of Medical Technology and Pharmacy, Da Nang, Viet Nam
  3. Department of Chemistry, Technical University of Berlin, Berlin, Germany
  4. Department of Chemistry and Centre for Pulse EPR Spectroscopy (PEPR), Imperial College London, London, United Kingdom
  5. Department of Biotechnology, Delft University of Technology, TU Delft, Delft, The Netherlands
  6. Comprehensive Cancer Center, King’s College London, London, United Kingdom

Hypoxia (low oxygen level) sensing is a fundamental cellular process contributing to many human diseases. Discoveries of hypoxia and its sensing through the hypoxia-inducible factor (HIF) pathway have provided significant knowledge of cellular responses to low oxygen conditions1. In this study, by applying an interdisciplinary approach, we investigate the reaction of molecular oxygen (O2) and gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) with mitoNEET, a [2Fe-2S] iron-sulfur protein located in the mitochondrial outer membrane. Our findings revealed that NO desensitises the mitoNEET [2Fe-2S] clusters towards reduction by H2S. We discovered a specific NO access tunnel to the [2Fe-2S] cluster and found that both O₂ and pioglitazone inhibited NO access to the mitoNEET [2Fe-2S] cluster2. Our findings suggest that the level of molecular O₂ modulates the gasotransmitter sensory action of mitoNEET. These findingshighlight a novel hypoxia-associated mechanism by which mitoNEET influences mitochondrial function and redox signalling (Figure 1), offering new perspectives on its involvement in hypoxia-related diseases such as type-2 diabetes.

 

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Figure 1. A schematic model describing the molecular function of mitoNEET [2Fe-2S] cluster in sensing O2 level and gasotransmitters. Under normoxic conditions, O2 protects the mitoNEET [2Fe-2S] cluster (left). Under inflammatory and hypoxic conditions (right), when the NO level rises, mitoNEET is oxidized by NO and desensitized to H2S reduction (grey). Pioglitazone protects the mitoNEET cluster against NO oxidation and enables H2S reduction (light greeen).

  1. Semenza, G.L. 'Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology’, Annual Review of Pathology: Mechanisms of Disease, 2014, 9(1), pp. 47–71.
  2. Hoang, T. N., Wu‐Lu, M., Collauto, A., Hagedoorn, P. L., Alexandru, M., Henschel, M., Korrdasti, S., Mroginski, M. A., Roessler, M. M. & Ebrahimi, K. H. The [2Fe‐2S] cluster of mitochondrial outer membrane protein mitoNEET has an O2‐regulated nitric oxide access tunnel, FEBS letters, 2025, doi:10.1002/1873-3468.15097.