TY - JOUR TI - Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins AU - Nowicka, Urszula AU - Chroscicki, Piotr AU - Stroobants, Karen AU - Sladowska, Maria AU - Turek, Michal AU - Uszczynska-Ratajczak, Barbara AU - Kundra, Rishika AU - Goral, Tomasz AU - Perni, Michele AU - Dobson, Christopher M AU - Vendruscolo, Michele AU - Chacinska, Agnieszka A2 - Schuldiner, Maya A2 - Ron, David A2 - Meisinger, Chris VL - 10 PY - 2021 DA - 2021/07/20 SP - e65484 C1 - eLife 2021;10:e65484 DO - 10.7554/eLife.65484 UR - https://doi.org/10.7554/eLife.65484 AB - 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. KW - mitochondria KW - aggregation KW - chaperones KW - neurodegeneration KW - homeostasis KW - metastable proteins JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -