Abstract 1457: Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits

Abstract

Abstract Introduction: The control of protein homeostasis, or proteostasis is essential for cellular adaptation to disparate environmental cues and relies on protein (re)folding or proteolytic removal of aggregated or misfolded proteins. Defective proteostasis can irreversibly impair organelle functions and activate cell death through an unfolded protein response. Tumor mitochondria have heightened protein folding quality control, but the regulators of this process and how they impact cancer traits are not completely understood. In this study, we investigated the mechanisms of stress-regulated LonP1 (ATP-dependent protease) in tumor mitochondria and their implications for advanced cancer traits. Experimental procedures: We monitored kinase activity in immunoprecipitation, protein expression by immunoblotting, mitochondrial ROS quantification in live cells, mitochondrial electron transport chain (ETC) activity, mitochondria time-lapse video microscopy, protein folding, proteomics analysis, mitochondrial bioenergetics, mitochondrial trafficking and tumor cell motility, and tumor growth and metastasis. A xenograft prostate cancer model was used to study antitumor activity in vivo. Results: We showed 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. Conclusion: These data identify LonP1 as a key effector of mitochondrial reprogramming in cancer and potential therapeutic target. Citation Format: Jagadish C. ghosh, Jae Ho Seo, Ekta Agarwal, Yuan Wang, Andrew V. Kossenkov, Hsin-Yao Tang, David W. Speicher, Dario C. Altieri. Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1457.