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Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol.

Wrobel, Lidia and Topf, Ulrike and Bragoszewski, Piotr and Wiese, Sebastian and Sztolsztener, Malgorzata E and Oeljeklaus, Silke and Varabyova, Aksana and Lirski, Maciej and Chroscicki, Piotr and Mroczek, Seweryn and Januszewicz, Elzbieta and Dziembowski, Andrzej and Koblowska, Marta and Warscheid, Bettina and Chacinska, Agnieszka (2015) Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature, 524 (7566). pp. 485-8. ISSN 1476-4687

[img] Microsoft Excel
[img] Microsoft Excel
[img] Microsoft Excel

Official URL: http://www.nature.com/nature/journal/v524/n7566/fu...


Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.

Item Type:Article
Subjects:Q Science > Q Science (General)
ID Code:1058
Deposited By: Maciej Lirski
Deposited On:09 Dec 2015 09:05
Last Modified:08 Mar 2018 15:33

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