title: ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity.
abstract: We generated mice deficient in Lon protease (LONP1), a major enzyme of the mitochondrial quality control machinery. Homozygous deletion of Lonp1 causes early embryonic lethality, whereas its haploinsufficiency protects against colorectal and skin tumors. Furthermore, LONP1 knockdown inhibits cellular proliferation and tumor and metastasis formation, whereas its overexpression increases tumorigenesis. Clinical studies indicate that high levels of LONP1 are a poor prognosis marker in human colorectal cancer and melanoma. Additionally, functional analyses show that LONP1 plays a key role in metabolic reprogramming by remodeling OXPHOS complexes and protecting against senescence. Our findings demonstrate the relevance of LONP1 for cellular and organismal viability and identify this protease as a central regulator of mitochondrial activity in oncogenesis.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Quirós
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Español
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Rodríguez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Clea
authors.initials: C
authors.lastname: Bárcena
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Kenta
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Cardiovascular Proteomics Laboratory, Department of Vascular Biology, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Cardiovascular Proteomics Laboratory, Department of Vascular Biology, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Loureiro
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: M Soledad
authors.initials: MS
authors.lastname: Fernández-García
authors.affiliation: Area de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fueyo
authors.affiliation: Cardiovascular Proteomics Laboratory, Department of Vascular Biology, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Enríquez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain. Electronic address: clo@uniovi.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D045325:HCT116 Cells; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006720:Homozygote; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D049069:ATP-Dependent Proteases