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.
Highlights
The control of protein homeostasis, or proteostasis, occupies a central, evolutionary-conserved role in organismal integrity and flexible adaptation to environmental “stress” [1]
As the powerhouse of the cell and a pivotal hub for oxidative stress, mitochondria must tightly control the state of the proteins that they contain, quickly eliminating misfolded, PLOS Biology | DOI:10.1371/journal.pbio
Mitochondrial Proteostasis in Metastasis (DCA), and a Challenge Award from the Prostate Cancer Foundation (PCF) to MCC, LRL, and DCA, Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute
Summary
The control of protein homeostasis, or proteostasis, occupies a central, evolutionary-conserved role in organismal integrity and flexible adaptation to environmental “stress” [1]. This pathway involves mechanisms of chaperone-directed protein (re)folding [2] as well as removal of aggregated or misfolded proteins via proteolytic degradation [3]. Molecular chaperones of the heat shock protein-90 (Hsp90) family, including Hsp90 [7] and its homolog, TNFR-associated molecule-1 (TRAP-1) [8], become overexpressed in mitochondria of tumor cells compared to normal tissues [9] and preserve the folding and activity of key effectors of organelle homeostasis [10]. The heightened proteostatic environment prevents the emergence of a mitochondrial UPR [11], antagonizes cyclophilin D-dependent apoptosis [9], and maintains bioenergetics [10], including oxidative phosphorylation [12], correlating with unfavorable disease outcome in cancer patients [13]
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