title: Cytosolic proteostasis through importing of misfolded proteins into mitochondria.
abstract: Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many neurodegenerative-disease-associated proteins can be found in mitochondria, it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins. Here we show that, in yeast, cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates that form under heat shock contain both cytosolic and mitochondrial proteins and interact with the mitochondrial import complex. Many aggregation-prone proteins enter the mitochondrial intermembrane space and matrix after heat shock, and some do so even without stress. Timely dissolution of cytosolic aggregates requires the mitochondrial import machinery and proteases. Blocking mitochondrial import but not proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells.
authors.affiliation: Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.|Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Linhao
authors.initials: L
authors.lastname: Ruan
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
authors.forename: Chuankai
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Erli
authors.initials: E
authors.lastname: Jin
authors.affiliation: Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.|Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Kucharavy
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, USA.|Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
mesh_terms: D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates / Q000502:physiology*; D017510:Protein Folding; D058849:Protein Refolding; D055550:Protein Stability; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D066329:Protein Aggregates; D011506:Proteins; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex