DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth

Jonathan Barra; Isaiah Crosbourne; Cassandra L. Roberge; Ramon Bossardi-Ramos; Janine S.A. Warren; Kailie Matteson; Ling Wang; Frances Jourd’heuil; Sergey M. Borisov; Erin Bresnahan; Jose Javier Bravo-Cordero; Ruslan I. Dmitriev; David Jourd’heuil; Alejandro P. Adam; John M. Lamar; David T. Corr; Margarida M. Barroso

doi:10.1038/s41388-023-02933-x

DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth

Jonathan Barra, Isaiah Crosbourne, Cassandra L. Roberge, Ramon Bossardi-Ramos, Janine S.A. Warren, Kailie Matteson, Ling Wang, Frances Jourd’heuil, Sergey M. Borisov, Erin Bresnahan, Jose Javier Bravo-Cordero, Ruslan I. Dmitriev, David Jourd’heuil, Alejandro P. Adam, John M. Lamar, David T. Corr, Margarida M. Barroso^*

^*Corresponding author for this work

Institute of Analytical Chemistry and Food Chemistry (6450)

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

Abstract

Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells. Mitochondrial bioenergetics and the iron-associated protein profile were altered by DMT1 silencing and rescued by DMT1 re-expression. Transcriptomic profiles upon DMT1 silencing are strikingly different between 2D and 3D culture conditions, suggesting that the environment context is crucial for the DMT1 knockout phenotype observed in MDA-MB-231 cells. Lastly, in vivo lung metastasis assay revealed that DMT1 silencing promoted the outgrowth of lung metastatic nodules in both human and murine models of triple-negative breast cancer cells. These findings reveal a DMT1‐dependent pathway connecting EE-mitochondria interactions to mitochondrial iron translocation and metastatic fitness of breast cancer cells.

Original language	English
Pages (from-to)	650-667
Number of pages	18
Journal	Oncogene
Volume	43
Issue number	9
DOIs	https://doi.org/10.1038/s41388-023-02933-x
Publication status	Published - 23 Feb 2024

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

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

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Barra, J., Crosbourne, I., Roberge, C. L., Bossardi-Ramos, R., Warren, J. S. A., Matteson, K., Wang, L., Jourd’heuil, F., Borisov, S. M., Bresnahan, E., Bravo-Cordero, J. J., Dmitriev, R. I., Jourd’heuil, D., Adam, A. P., Lamar, J. M., Corr, D. T., & Barroso, M. M. (2024). DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth. Oncogene, 43(9), 650-667. https://doi.org/10.1038/s41388-023-02933-x

Barra, J, Crosbourne, I, Roberge, CL, Bossardi-Ramos, R, Warren, JSA, Matteson, K, Wang, L, Jourd’heuil, F, Borisov, SM, Bresnahan, E, Bravo-Cordero, JJ, Dmitriev, RI, Jourd’heuil, D, Adam, AP, Lamar, JM, Corr, DT & Barroso, MM 2024, 'DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth', Oncogene, vol. 43, no. 9, pp. 650-667. https://doi.org/10.1038/s41388-023-02933-x

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title = "DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth",

abstract = "Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells. Mitochondrial bioenergetics and the iron-associated protein profile were altered by DMT1 silencing and rescued by DMT1 re-expression. Transcriptomic profiles upon DMT1 silencing are strikingly different between 2D and 3D culture conditions, suggesting that the environment context is crucial for the DMT1 knockout phenotype observed in MDA-MB-231 cells. Lastly, in vivo lung metastasis assay revealed that DMT1 silencing promoted the outgrowth of lung metastatic nodules in both human and murine models of triple-negative breast cancer cells. These findings reveal a DMT1‐dependent pathway connecting EE-mitochondria interactions to mitochondrial iron translocation and metastatic fitness of breast cancer cells. ",

author = "Jonathan Barra and Isaiah Crosbourne and Roberge, {Cassandra L.} and Ramon Bossardi-Ramos and Warren, {Janine S.A.} and Kailie Matteson and Ling Wang and Frances Jourd{\textquoteright}heuil and Borisov, {Sergey M.} and Erin Bresnahan and Bravo-Cordero, {Jose Javier} and Dmitriev, {Ruslan I.} and David Jourd{\textquoteright}heuil and Adam, {Alejandro P.} and Lamar, {John M.} and Corr, {David T.} and Barroso, {Margarida M.}",

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AU - Barra, Jonathan

AU - Crosbourne, Isaiah

AU - Roberge, Cassandra L.

AU - Bossardi-Ramos, Ramon

AU - Warren, Janine S.A.

AU - Matteson, Kailie

AU - Wang, Ling

AU - Jourd’heuil, Frances

AU - Borisov, Sergey M.

AU - Bresnahan, Erin

AU - Bravo-Cordero, Jose Javier

AU - Dmitriev, Ruslan I.

AU - Jourd’heuil, David

AU - Adam, Alejandro P.

AU - Lamar, John M.

AU - Corr, David T.

AU - Barroso, Margarida M.

PY - 2024/2/23

Y1 - 2024/2/23

N2 - Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells. Mitochondrial bioenergetics and the iron-associated protein profile were altered by DMT1 silencing and rescued by DMT1 re-expression. Transcriptomic profiles upon DMT1 silencing are strikingly different between 2D and 3D culture conditions, suggesting that the environment context is crucial for the DMT1 knockout phenotype observed in MDA-MB-231 cells. Lastly, in vivo lung metastasis assay revealed that DMT1 silencing promoted the outgrowth of lung metastatic nodules in both human and murine models of triple-negative breast cancer cells. These findings reveal a DMT1‐dependent pathway connecting EE-mitochondria interactions to mitochondrial iron translocation and metastatic fitness of breast cancer cells.

AB - Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells. Mitochondrial bioenergetics and the iron-associated protein profile were altered by DMT1 silencing and rescued by DMT1 re-expression. Transcriptomic profiles upon DMT1 silencing are strikingly different between 2D and 3D culture conditions, suggesting that the environment context is crucial for the DMT1 knockout phenotype observed in MDA-MB-231 cells. Lastly, in vivo lung metastasis assay revealed that DMT1 silencing promoted the outgrowth of lung metastatic nodules in both human and murine models of triple-negative breast cancer cells. These findings reveal a DMT1‐dependent pathway connecting EE-mitochondria interactions to mitochondrial iron translocation and metastatic fitness of breast cancer cells.

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DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth

Abstract

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UN SDGs

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