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

eLife

Piotr Chroscicki¹  Christopher M Dobson¹  Karen Stroobants²  Tomasz Goral³  Michal Turek³  Michele Vendruscolo³  Barbara Uszczynska-Ratajczak⁴  Agnieszka Chacinska⁵  Rishika Kundra⁵  Maria Sladowska⁵  Michele Perni⁶  Urszula Nowicka⁶ 

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

关键词: mitochondria;    aggregation;    chaperones;    neurodegeneration;    homeostasis;    metastable proteins;   

DOI  :  10.7554/eLife.65484

来源: DOAJ

【 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】

Unknown