title: Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmtto promote metastasis.
abstract: By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPRmt). The UPRmtpromotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPRmt, we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPRmtis a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Kenny
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hart
authors.affiliation: Pathology Unit, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ragazzi
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sersinghe
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chipuk
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, WI, USA.
authors.forename: M A K
authors.initials: MAK
authors.lastname: Sagar
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, WI, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: LaFramboise
authors.affiliation: Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Grandhi
authors.affiliation: National Institute of Environmental Health Sciences, Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Santos
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Riar
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Papa
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: D'Aurello
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Manfredi
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Bonini
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Germain
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000502:physiology*; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D009362:Neoplasm Metastasis; D056566:Sirtuin 3 / Q000502:physiology*; D013482:Superoxide Dismutase / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D000099156:Superoxide Dismutase 2
chemical_list: D004272:DNA, Mitochondrial; D000071316:Forkhead Box Protein O3; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C499517:FOXO3 protein, human; C466093:SIRT3 protein, human