# The role of mitochondrial glutathione homeostasis in tumor formation

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $466,306

## Abstract

Project Summary
 Cancer cells require substantial antioxidant capacity to overcome toxic effects of reactive oxygen species
(ROS). Despite their exclusive cytosolic production, cellular antioxidants are also abundantly present in
organelles, particularly in mitochondria. In particular, mitochondria, as the source of reactive oxygen species
(ROS), require substantial availability of antioxidants to protect its critical redox functions. While previous work
suggests a link between mitochondrial redox metabolism and tumor growth, molecular mechanisms involved in
maintaining mitochondrial redox homeostasis and the role of mitochondrial antioxidants in tumor progression
are poorly understood. Among endogenous mitochondrial antioxidants, glutathione (GSH) is the dominant small
molecule thiol, existing in millimolar concentrations. GSH is commonly upregulated in cancer cells, enabling
metastatic colonization and resistance to chemotherapeutic drugs. In our previous work, using biochemical and
proteomics methods, we identified SLC25A39, a mitochondrial membrane carrier of unknown function, to
mediate GSH import into mitochondria of cancer cells. SLC25A39 loss strongly reduces mitochondrial GSH
levels and its import, without impacting those in the cytosol. Our preliminary work suggests that SLC25A39
expression is associated with poor prognosis and decreased survival of breast cancer patients, and that
SLC25A39 is necessary for breast cancer invasion and metastasis. This finding gave us the opportunity, for the
first time, to uncouple mitochondrial redox metabolism from that of cytosol during tumor progression. Building
upon this evidence, in this proposal, we will test the hypothesis that mitochondrial GSH import by SLC25A39
enables metastatic colonization of breast cancer cells. To address this, using biochemical and genetic
experiments, we will first identify the precise mechanism by which mitochondrial GSH enables breast cancer
cells to metastasize to lung. We will then test the role of mitochondrial GSH import by SLC25A39 in tumor
formation and metastasis using mouse and human breast cancer models. Finally, SLC25A39 protein levels
substantially increase during lung colonization, indicating a strong selective pressure to induce mitochondrial
GSH uptake during metastasis. Therefore, we will determine how mitochondrial GSH availability and lung
environment regulate SLC25A39 protein levels in breast cancer cells. This proposal will reveal the role of
mitochondrial GSH homeostasis in breast cancer progression and will identify a compartmentalized sensing
pathway essential for metastatic colonization.

## Key facts

- **NIH application ID:** 10817941
- **Project number:** 5R01CA273233-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Kivanc Birsoy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,306
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817941

## Citation

> US National Institutes of Health, RePORTER application 10817941, The role of mitochondrial glutathione homeostasis in tumor formation (5R01CA273233-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10817941. Licensed CC0.

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