Cytosolic Proteostasis via Importing of Misfolded Proteins into Mitochondria
By Linhao Ruan, Chuankai Zhou, Erli Jin, Andrei Kucharavy, Ying Zhang, Zhihui Wen, L. Florens, Rong Li. Nature, 2017
321 citations recorded by the source corpus.
Loss of proteostasis underlies ageing and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction. Although many neurodegenerative-disease-associated proteins can be found in mitochondria, it remains unclear how mitochondrial dysfunction and protein aggregation could be related. In dividing yeast cells, protein aggregates that form under stress or during ageing are preferentially retained by the mother cell, in part through tethering to mitochondria, while the disaggregase Hsp104 helps to dissociate aggregates and thereby enables refolding or degradation of misfolded proteins. Here we show that, in yeast, cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates that form under heat shock contain both cytosolic and mitochondrial proteins and interact with the mitochondrial import complex. Many aggregation-prone proteins enter the mitochondrial intermembrane space and matrix after heat shock, and some do so even without stress. Timely dissolution of cytosolic aggregates requires the mitochondrial import machinery and proteases. Blocking mitochondrial import but not proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells.
Subfields: Cell Biology, Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/535204a5788239343cc27497f50f9639892f4f02
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Citations in the corpus
- TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “TDP-43 entry into mitochondria appears to be highly conserved evolutionarily, with evidence of this in yeast (Ruan et al., 2017) and demonstrated for mice in vivo (Davis et al.”