Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins

eLife

Karen Stroobants¹  Michele Vendruscolo¹  Christopher M Dobson¹  Michele Perni¹  Rishika Kundra¹  Barbara Uszczynska-Ratajczak²  Maria Sladowska³  Piotr Chroscicki³  Tomasz Goral⁴  Urszula Nowicka⁵  Agnieszka Chacinska⁵  Michal Turek⁶ 

[1] Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom;Centre of New Technologies, University of Warsaw, Warsaw, Poland;Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland;Centre of New Technologies, University of Warsaw, Warsaw, Poland;International Institute of Molecular and Cell Biology, Warsaw, Poland;ReMedy International Research Agenda Unit, University of Warsaw, Warsaw, Poland;Centre of New Technologies, University of Warsaw, Warsaw, Poland;ReMedy International Research Agenda Unit, University of Warsaw, Warsaw, Poland;Centre of New Technologies, University of Warsaw, Warsaw, Poland;IMol Polish Academy of Sciences, Warsaw, Poland;ReMedy International Research Agenda Unit, University of Warsaw, Warsaw, Poland;Centre of New Technologies, University of Warsaw, Warsaw, Poland;International Institute of Molecular and Cell Biology, Warsaw, Poland;

关键词: mitochondria;    aggregation;    chaperones;    neurodegeneration;    homeostasis;    metastable proteins;    S. cerevisiae;    C. elegans;   

DOI  :  10.7554/eLife.65484

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.

【 授权许可】

CC BY