Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins
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Peer-reviewed
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Abstract
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.
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Funder: William B. Harrison Foundation
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National Science Centre (2015/18/A/NZ1/00025)
Polish Ministerial Funds for Science (Ideas Plus programme 000263)
Deutsche Forschungsgemeinschaft (Copernicus Award)
Foundation for Polish Science (Copernicus Award)
Foundation for Polish Science (HOMING POIR.04.04.00-00-3FE4/17 (co-financed by the European Union under the European Regional Development Fund))
National Science Centre (POLONEZ 2016/23/P/NZ3/03730 (European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 665778))
National Science Centre (POLONEZ UMO-2016/21JPJNZ3/03891 (European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 665778))
EMBO (7124)
University of Cambridge (Centre for Misfolding Diseases)