An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.

Autor:	Miallot R; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France miallot@ciml.univ-mrs.fr., Millet V; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Groult Y; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Modelska A; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Crescence L; Aix Marseille Université, INSERM 1263, INRAE 1260, Plateforme d'Imagerie Vasculaire et de Microscopie Intravitale, C2VN, Marseille, France., Roulland S; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Henri S; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Malissen B; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France.; Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, Marseille, France., Brouilly N; Aix-Marseille Université, CNRS, IBDM, Marseille, France., Panicot-Dubois L; Aix Marseille Université, INSERM 1263, INRAE 1260, Plateforme d'Imagerie Vasculaire et de Microscopie Intravitale, C2VN, Marseille, France., Vincentelli R; Aix-Marseille Université, CNRS, Architecture et Fonction des Macromolécules Biologiques, Marseille, France., Sulzenbacher G; Aix-Marseille Université, CNRS, Architecture et Fonction des Macromolécules Biologiques, Marseille, France., Finetti P; Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France., Dutour A; Childhood Cancers and Cell Death Laboratory, Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS, Lyon, France., Blay JY; Childhood Cancers and Cell Death Laboratory, Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS, Lyon, France.; Department of Medicine, Centre Léon Bérard, UNICANCER & University Lyon I, Lyon, France., Bertucci F; Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille, France., Galland F; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France., Naquet P; Aix-Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, Marseille, France naquet@ciml.univ-mrs.fr.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2023 Apr 05; Vol. 6 (6). Date of Electronic Publication: 2023 Apr 05 (Print Publication: 2023).
DOI:	10.26508/lsa.202201767
Abstrakt:	Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell-deficient, mice. These cells prime CD8 + lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity. (© 2023 Miallot et al.)
Databáze:	MEDLINE
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