Dataset Information

ROSALIND protects the mitochondrial translational machinery from oxidative damage

ABSTRACT: Cancer therapy resistance, whether pre-existing or arising upon acquisition of de novo mutations and via non-genetic adaptation, is still 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 with this, upregulation of mitochondrial respiration coupled with 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 an 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 increases 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Neoplastic

DISEASE(S): Melanoma

SUBMITTER: Vasiliki Katopodi

LAB HEAD: Eleonora Leucci

PROVIDER: PXD047963 | Pride | 2024-09-20

REPOSITORIES: Pride

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The long non-coding RNA ROSALIND protects the mitochondrial translational machinery from oxidative damage.

Katopodi Vicky V Marino Alessandro A Pateraki Nikoleta N Verheyden Yvessa Y Cinque Sonia S Jimenez Elena Lara EL Adnane Sara S Demesmaeker Ewout E Scomparin Alice A Derua Rita R Groaz Elisabetta E Leucci Eleonora E

Cell death and differentiation 20240918

Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognising and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity li ...[more]

PMID: 39294440

Similar Datasets

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.

Project description:Intermittent hypoxia is a common stressor in estuarine and coastal habitats due to the diurnal and tidal cycles of oxygen availability. Oxygen deficiency results in energy stress by limiting aerobic ATP production, while reoxygenation may lead to oxidative injury due to the excessive production of reactive oxygen species (ROS) in mitochondria. Mitochondria are a key intracellular target of hypoxia-reoxygenation (H/R) stress due to their central role in ATP production, ROS generation and stress signaling. Marine intertidal bivalves such as the Pacific oyster Crassostrea gigas are adapted to frequent H/R cycles in the intertidal zone and maintain mitochondrial integrity and aerobic function despite frequent oxygen fluctuations. To gain insight into the molecular responses of mitochondria of the hypoxia-tolerant Pacific oyster to H/R stress, we studied changes in oxidative phosphorylation (OXPHOS) capacity, proton leak and activity of the electron transport system enzymes (ETS) in gill mitochondria of C. gigas. We furthermore investigated shifts in mitochondrial proteome and phosphoproteome after 24 h of hypoxia and 1 h of post-hypoxic recovery. Oyster mitochondria maintained normal ETS and OXPHOS capacity during H/R stress, despite a slight but significant decline in cytochrome c oxidase (Complex IV) activity after reoxygenation. Fifty total proteins and 36 phosphoproteins were differentially abundant in mitochondria of H/R exposed oysters compared with the controls. Rearrangements of the mitochondrial (phospho)proteome during H/R stress involved upregulation of mitochondrial ETS (most notably Complexes I and IV) and iron-binding proteins (frataxin and ferrochelatase) as well as suppression of the metabolic pathways that channel electrons to ubiquinone, possibly as a mechanism to limit ROS production due to the iron overload and reverse flow of electrons through ETS. H/R stress also led to upregulation of a mitophagic activator serine/threonine protein phosphatase PGAM5 and dephosphorylation of metalloendopeptidase OMA1 indicating stimulation of mitochondrial quality control mechanisms during reoxygenation. Changes in the overall abundance and phosphorylation levels of several key proteins involved in the mitochondrial protein homeostasis (including subunits of the mitochondrial ribosome, mitochondrial inner membrane translocase and elongation factor G) are consistent with the suppression of the protein synthesis during hypoxia, likely as an energy-saving mechanism. Overall, our study indicates that shifts in the mitochondrial (phospho-)proteome play an important role in responses of oysters to H/R stress and might complement adaptations of anaerobic metabolism and metabolic rate depression in ensuring hypoxic survival and rapid recovery in this hypoxia-tolerant intertidal species.