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.
Highlights
Over one thousand proteins are utilized by mitochondria to perform their functions, only ~1% of them are synthesized inside this organelle
The present study showed that a group of mitochondrial proteins that are downregulated in Alzheimer’s disease (i.e., Rip1, Atp2, Cox8, and Atp20) can aggregate in the cytosol and that the overexpression of these proteins upregulates Hsp42 and Hsp104, two molecular chaperones that are associated with inclusion bodies (Balchin et al, 2016; Mogk et al, 2015; Mogk et al, 2019)
Our findings of modulated aggregate-related chaperones upregulation further contribute to the transcriptomic response mechanisms involving chaperones due to mitochondrial import machinery overload (Boos et al, 2019), and mechanism of proteasomal protein degradation machinery upregulation (Wrobel et al, 2015)
Summary
Over one thousand proteins are utilized by mitochondria to perform their functions, only ~1% of them are synthesized inside this organelle. Impairments in mitochondrial protein import and mitochondrial import machinery overload result in the accumulation of mitochondria-targeted proteins in the cytosol and stimulation of mitoprotein-induced stress (Boos et al, 2019; Wang & Chen, 2015; Wrobel et al, 2015). These findings raise the issue of whether the accumulation of mistargeted mitochondrial proteins contributes to the progression of neurodegenerative diseases. Our results showed that when some of these mitochondrial proteins remain in the cytosol because of mitochondrial protein import insufficiency, they formed insoluble aggregates that disrupted protein homeostasis These proteins triggered a prompt specific molecular chaperone response that aimed to minimize the consequences of protein aggregation. Our findings indicate that metastable mitochondrial proteins can be transcriptionally downregulated during neurodegeneration to minimize cellular protein homeostasis imbalance that is caused by their mistargeting
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