Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

S Garciaz; AA Guirguis; S Müller; FC Brown; YC Chan; A Motazedian; CL Rowe; JA Kuzich; KL Chan; K Tran; L Smith; L Macpherson; B Liddicoat; EYN Lam; T Cañeque; ML Burr; V Litalien; G Pomilio; M Poplineau; E Duprez; SJ Dawson; G Ramm; AG Cox; KK Brown; DCS Huang; AH Wei; K McArthur; R Rodriguez; MA Dawson

Journal article

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

S Garciaz, AA Guirguis, S Müller, FC Brown, YC Chan, A Motazedian, CL Rowe, JA Kuzich, KL Chan, K Tran, L Smith, L Macpherson, B Liddicoat, EYN Lam, T Cañeque, ML Burr, V Litalien, G Pomilio, M Poplineau, E Duprez Show all

Cancer Discovery | Published : 2022

DOI: 10.1158/2159-8290.CD-21-0522

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Abstract

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways ..

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University of Melbourne Researchers

Chih Chan Author

Ali Motazedian Author

Jamie Kuzich Author

Kah Lok Chan Author

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Grants

Awarded by Ligue Contre le Cancer

Funding Acknowledgements

This study was supported by NHMRC Investigator Grant (#1196749, to M.A. Dawson), Cancer Council Victoria Dunlop Fellowship (to M.A. Dawson), Howard Hughes Medical Institute international research scholarship (#55008729, to M.A. Dawson), NHMRC Investigator Grant (#1196755, to S.J. Dawson), and CSL Centenary fellowship (to S.J. Dawson) The R. Rodriguez research group is funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 647973), the Fondation Charles Defforey-Institut de France, Ligue Contre le Cancer (Equipe Labellisee), and Region Ile-de-France. A.G. Cox was supported by an NHMRC Investigator Grant (GNT1176732) and an ARC Discovery Project Grant (DP200102693). K.K. Brown was supported by an NHMRC Project Grant (GNT1146642), a VCA Mid-Career Research Fellowship (MCRF17020), and a Susan G. Komen Career Catalyst Research Grant (CCR18548354). We thank members of the Dawson laboratory, particularly Susan Jackson for technical assistance with experiments. We thank the ICP-MS platform at the Institut de Physique du Globe de Paris. This research used National Collaborative Research Infrastructure Strategy (NCRIS)-enabled Metabolomics Australia infrastructure at the University of Melbourne, funded through BioPlatforms Australia. We thank members of the Y. Collette laboratory and the TrGET Platform, particularly C. Montersino for technical assistance with experiments. We acknowledge S. Anthony and T.L. Saunders for experimental assistance and G. Brumatti for providing Birinapant and IDN-6556. S. Garciaz thanks Nuovo-Soldati for Cancer Research and Fondation de France for the received grants.