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Oxidation of Retromer Complex controls Mitochondrial Translation

ABSTRACT: Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration. The mitochondrial electron transport chain is appreciated as a key regulator of ROS stoichiometry in cells. However, the pathways that sense and regulate ROS levels more broadly remain to be fully elucidated. Here, systematic base-editor and computational screens identify VPS35, a member of the Retromer trafficking complex, as a cytosolic ROS sensor. Mechanistically, we find that VPS35 C653/C673 regulates compartmentalized mitochondrial translation by disrupting the plasma membrane localization of SLC7A1, leading to dramatic resistance against ROS-generating anti-cancer agents including cisplatin. Our study describes the regulation of compartmentalized translation and cellular ROS homeostasis by a single amino acid within vesicular trafficking machinery, supporting the long-standing hypothesis that mitochondrial ROS is implicated in cisplatin resistance. We anticipate that the approaches employed herein may template a generalizable method for the identification of functional ROS targets and sensors under various biological contexts.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Liron Bar-Peled

PROVIDER: MSV000096912 | MassIVE | Wed Jan 22 11:55:00 GMT 2025

SECONDARY ACCESSION(S): PXD060069

REPOSITORIES: MassIVE

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Project description:Cancer therapy resistance, whether it is pre-existing, emerges after acquiring de novo mutations, or occurs through non-genetic adaptationwhether pre-existing or arising following the acquisition of de novo mutations and via non-genetic adaptation , is stillremains a clinical challenge. Multiple anticancer drugs are thought to cause cell death via increasing mitochondrial ROS which are a bioproduct of oxidative phosphorylation. However, when properly titrated, ROS can also promote cancer cell adaptation. In keeping line with this, upregulation of mitochondrial respiration coupled to high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. Translational fidelity in the mitochondria and in the cytosol is essential for cell fitness and thus oxidative damage to the ribosomes should be prevented at all costs. While mechanisms for recognizing and repairing such damage exist in the cytoplasm, the status within mitochondria remains unclear. By performing ascorbate peroxidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear encoded lncRNA ROSALIND as a interacting partner of ribosomes. ROSALIND is upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content, ROSALIND serves as a substrate for oxidation. Consequently, inhibiting ROSALIND leads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and immunogenicity both in vitro and ex vivo in preclinical humanized cancer models. These findings underscore the role of ROSALIND as a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.

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Oxidation of Retromer Complex controls Mitochondrial Translation

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