Akt Phosphorylation of Mitochondrial Lonp1 Protease Enables Oxidative Metabolism and Advanced Tumor Traits

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2019 Aug 14

PMID 31406245

Citations 29

Authors

Jagadish C Ghosh

Jae Ho Seo

Ekta Agarwal

Yuan Wang

Andrew V Kossenkov

Hsin-Yao Tang

David W Speicher

Dario C Altieri

Affiliations

Soon will be listed here.

Abstract

Tumor mitochondria have heightened protein folding quality control, but the regulators of this process and how they impact cancer traits are not completely understood. Here we show that the ATP-directed mitochondrial protease, LonP1 is upregulated by stress conditions, including hypoxia, in tumor, but not normal cells. In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. Interference with this pathway induces accumulation of misfolded subunits of electron transport chain complex II and complex V, resulting in impaired oxidative bioenergetics and heightened ROS production. Functionally, this suppresses mitochondrial trafficking to the cortical cytoskeleton, shuts off tumor cell migration and invasion, and inhibits primary and metastatic tumor growth, in vivo. These data identify LonP1 as a key effector of mitochondrial reprogramming in cancer and potential therapeutic target.

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