Dataset Information

The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage

ABSTRACT: The metabolic plasticity of mitochondria supports cell development and differentiation and ensures cell survival under stress. The peptidase OMA1 regulates mitochondrial morphology and stress signaling and orchestrates tumorigenesis and cell fate decisions in a cell and tissue-specific manner. Here, we have used unbiased systemic approaches to demonstrate that OMA1-dependent cell fate decisions are under metabolic control. A metabolism-focus CRISPR screen combined with an integrated analysis of human expression data unraveled a protective role of OMA1 against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote the selective, p53-dependent apoptosis of cells lacking OMA1. The protective effect of OMA1 does not depend on OMA1 activation nor on OMA1-mediated OPA1 and DELE1 processing. OMA1-deficient cells have reduced glycolytic capacity and accumulate OXPHOS proteins upon DNA damage. OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. Thus, metabolic cues determine cell fate decisions by OMA1, which sheds new light on the role of OMA1 in cancerogenesis.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Hendrik Nolte

LAB HEAD: Thomas Langer

PROVIDER: PXD036595 | Pride | 2023-04-04

REPOSITORIES: pride

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Publications

The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.

Rivera-Mejías Pablo P Narbona-Pérez Álvaro Jesús ÁJ Hasberg Lidwina L Kroczek Lara L Bahat Amir A Lawo Steffen S Folz-Donahue Kat K Schumacher Anna-Lena AL Ahola Sofia S Mayer Fiona Carola FC Giavalisco Patrick P Nolte Hendrik H Lavandero Sergio S Langer Thomas T

Cell reports 20230331 4

The metabolic plasticity of mitochondria ensures cell development, differentiation, and survival. The peptidase OMA1 regulates mitochondrial morphology via OPA1 and stress signaling via DELE1 and orchestrates tumorigenesis and cell survival in a cell- and tissue-specific manner. Here, we use unbiased systems-based approaches to show that OMA1-dependent cell survival depends on metabolic cues. A metabolism-focused CRISPR screen combined with an integrated analysis of human gene expression data fo ...[more]

PMID: 37002921

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Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.

Dataset Information

The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage

Publications

The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage.

Similar Datasets

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