title: Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
abstract: The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes.
authors.affiliation: 1] German Center for Neurodegenerative Diseases, Tübingen, Germany [2] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: L F
authors.initials: LF
authors.lastname: Burbulla
authors.affiliation: 1] German Center for Neurodegenerative Diseases, Tübingen, Germany [2] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Fitzgerald
authors.affiliation: 1] German Center for Neurodegenerative Diseases, Tübingen, Germany [2] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany [3] Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stegen
authors.affiliation: 1] German Center for Neurodegenerative Diseases, Tübingen, Germany [2] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany [3] Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Westermeier
authors.affiliation: Autophagy Laboratory, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: A-K
authors.initials: AK
authors.lastname: Thost
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.affiliation: Adolf Butenandt Institute, Physiological Chemistry, University of Munich, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Mokranjac
authors.affiliation: 1] German Center for Neurodegenerative Diseases, Tübingen, Germany [2] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sauerwald
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Woitalla
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Rapaport
authors.affiliation: Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Riess
authors.affiliation: Autophagy Laboratory, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Proikas-Cezanne
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: T M
authors.initials: TM
authors.lastname: Rasse
authors.affiliation: 1] German Center for Neurodegenerative Diseases, Tübingen, Germany [2] Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany [3] Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Krüger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D053148:Caspase 3; D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D011494:Protein Kinases; D020123:Sirolimus; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C080352:mortalin; C111567:parkin protein
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