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PLoS Biol. 2016 Jul 7;14(7):e1002507. doi: 10.1371/journal.pbio.1002507. eCollection 2016 Jul.

The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis.

Author information

1
Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
2
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
3
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
4
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
5
Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
6
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
7
Division of Thoracic Surgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
8
Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
9
Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.

Abstract

Mitochondria must buffer the risk of proteotoxic stress to preserve bioenergetics, but the role of these mechanisms in disease is poorly understood. Using a proteomics screen, we now show that the mitochondrial unfoldase-peptidase complex ClpXP associates with the oncoprotein survivin and the respiratory chain Complex II subunit succinate dehydrogenase B (SDHB) in mitochondria of tumor cells. Knockdown of ClpXP subunits ClpP or ClpX induces the accumulation of misfolded SDHB, impairing oxidative phosphorylation and ATP production while activating "stress" signals of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy. Deregulated mitochondrial respiration induced by ClpXP targeting causes oxidative stress, which in turn reduces tumor cell proliferation, suppresses cell motility, and abolishes metastatic dissemination in vivo. ClpP is universally overexpressed in primary and metastatic human cancer, correlating with shortened patient survival. Therefore, tumors exploit ClpXP-directed proteostasis to maintain mitochondrial bioenergetics, buffer oxidative stress, and enable metastatic competence. This pathway may provide a "drugable" therapeutic target in cancer.

PMID:
27389535
PMCID:
PMC4936714
DOI:
10.1371/journal.pbio.1002507
[Indexed for MEDLINE]
Free PMC Article

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