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

Autor
Goral, Tomasz
Perni, Michele
Turek, Michał
Kundra, Rishika
Stroobants, Karen
Chacinska, Agnieszka
Sladowska, Maria
Nowicka, Urszula
Dobson, Christopher M
Chroscicki, Piotr
Data publikacji
2021
Abstrakt (EN)

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.

Słowa kluczowe EN
C. elegans
S. cerevisiae
aggregation
biochemistry
chaperones
chemical biology
homeostasis
metastable proteins
mitochondria
neurodegeneration
Dyscyplina PBN
nauki biologiczne
Czasopismo
eLife
Tom
10
ISSN
2050-084X
Licencja otwartego dostępu
Uznanie autorstwa- Bez utworów zależnych