title: The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis.
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.
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dayana B
authors.initials: DB
authors.lastname: Rivadeneira
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Caino
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Young Chan
authors.initials: YC
authors.lastname: Chae
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hsin-Yao
authors.identifier: 0000-0003-1838-018X
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.affiliation: Division of Thoracic Surgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alessandro
authors.identifier: 0000-0003-4510-5167
authors.initials: A
authors.lastname: Palleschi
authors.affiliation: Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rampini
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049071:Endopeptidase Clp / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D014183:Transplantation, Heterologous
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; C491545:SDHD protein, human; D000077022:Survivin; D013385:Succinate Dehydrogenase; C568646:ClpP protein, human; D049071:Endopeptidase Clp; C528384:CLPX protein, human