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AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS

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, b...

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Autores principales: Ghosh, Jagadish C., Seo, Jae Ho, Agarwal, Ekta, Wang, Yuan, Kossenkov, Andrew V., Tang, Hsin-Yao, Speicher, David W., Altieri, Dario C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814529/
https://www.ncbi.nlm.nih.gov/pubmed/31406245
http://dx.doi.org/10.1038/s41388-019-0939-7
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author Ghosh, Jagadish C.
Seo, Jae Ho
Agarwal, Ekta
Wang, Yuan
Kossenkov, Andrew V.
Tang, Hsin-Yao
Speicher, David W.
Altieri, Dario C.
author_facet Ghosh, Jagadish C.
Seo, Jae Ho
Agarwal, Ekta
Wang, Yuan
Kossenkov, Andrew V.
Tang, Hsin-Yao
Speicher, David W.
Altieri, Dario C.
author_sort Ghosh, Jagadish C.
collection PubMed
description 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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spelling pubmed-68145292020-02-12 AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS Ghosh, Jagadish C. Seo, Jae Ho Agarwal, Ekta Wang, Yuan Kossenkov, Andrew V. Tang, Hsin-Yao Speicher, David W. Altieri, Dario C. Oncogene Article 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. 2019-08-12 2019-10 /pmc/articles/PMC6814529/ /pubmed/31406245 http://dx.doi.org/10.1038/s41388-019-0939-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ghosh, Jagadish C.
Seo, Jae Ho
Agarwal, Ekta
Wang, Yuan
Kossenkov, Andrew V.
Tang, Hsin-Yao
Speicher, David W.
Altieri, Dario C.
AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS
title AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS
title_full AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS
title_fullStr AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS
title_full_unstemmed AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS
title_short AKT PHOSPHORYLATION OF MITOCHONDRIAL LonP1 PROTEASE ENABLES OXIDATIVE METABOLISM AND ADVANCED TUMOR TRAITS
title_sort akt phosphorylation of mitochondrial lonp1 protease enables oxidative metabolism and advanced tumor traits
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814529/
https://www.ncbi.nlm.nih.gov/pubmed/31406245
http://dx.doi.org/10.1038/s41388-019-0939-7
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