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: Pedro M Quirós, Yaiza Español, Rebeca Acín-Pérez, Francisco Rodríguez, Clea Bárcena, Kenta Watanabe, Enrique Calvo, Marta Loureiro, M Soledad Fernández-García, Antonio Fueyo, Jesús Vázquez, José Antonio Enríquez, Carlos López-Otín
• Journal: Cell reports (Cell Rep) Vol. 8 Issue 2 Pg. 542-56 (Jul 24 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25017063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• ATP-Dependent Proteases

Topics

• ATP-Dependent Proteases (genetics, metabolism)
• Animals
• Cell Proliferation
• Cellular Senescence (genetics)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Gene Deletion
• HCT116 Cells
• HEK293 Cells
• Haploinsufficiency
• Homozygote
• Humans
• Melanoma (genetics, metabolism, pathology)
• Mice
• Mitochondria (metabolism)
• Oxidative Phosphorylation
• Skin Neoplasms (genetics, metabolism, pathology)