Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating other proteins aggregation
Posted on: 20 May 2021 , updated on: 21 May 2021
Preprint posted on 2 May 2021
Article now published in eLife at http://dx.doi.org/10.7554/eLife.65484
Defective mitochondrial protein import creates a snowball-like aggregation mechanism: a potential connection between mitochondrial dysfunction and neurodegeneration
Selected by Eric McGregor
Categories: cell biology, molecular biology, pathology
Background:
Mitochondria are the key energy producers of a cell. This energy production requires the presence of several proteins and protein complexes, some of which are encoded by the mitochondrial genome. However, the majority are encoded by nuclear DNA and have to be imported into the mitochondria. This import process requires an intricate system of protein translocases, targeting signals, and sorting machinery1. The inability to efficiently traffic proteins from the cytosol into the mitochondria can lead to severely impaired function2, and mitochondrial dysfunction is a prominent hallmark of many neurodegenerative disorders.
Disease-related proteins such as amyloid-beta and alpha-synuclein have been shown to interfere with mitochondrial import and subsequent protein processing3,4. However, whether mitochondrial defects are causal in neurodegenerative disorders, caused by other pathological symptoms of the neurodegenerative disorders, or both, remains to be elucidated. It was previously shown that protein import impairment leads to the accumulation of mitochondrial proteins in the cytosol2. In this preprint, Nowicka et al. investigate whether the cytosolic accumulation of these mitochondrial proteins serves as a triggering event for the aggregation of disease-related proteins.
Key Findings:
1.) Metastable mitochondrial precursor proteins can aggregate in the cytosol
Previous work done in the Vendruscolo lab had found oxidative phosphorylation to be downregulated in the central nervous system of Alzheimer’s disease patients5,6. Because of these findings, the authors of this preprint used KEGG pathway analysis to identify mitochondrial genes for further investigation. To do this, they began their study in yeast, a widely used model organism in proteostasis and aging biology. They then designed a centrifugation assay to investigate whether overexpression of their proteins-of-interest led to their subsequent aggregation. Atp2 and Atp20 (2 subunits of ATP synthase), Rieske iron-sulfur ubiquinol-cytochrome c reductase (Rip1), and Cox8 were insoluble and therefore aggregating. Multiple components of the cytochrome c reductase complex were also found to be partially insoluble. The researchers then used two models of mitochondrial protein import impairment, chemical and genetic, to observe which precursors would aggregate in response. They observed the cytosolic accumulation of the precursors of Rip1 (pRip1), superoxide dismutase (pSod2), and mitochondrial malate dehydrogenase 1 (pMdh1) under both conditions.
2.) Mitochondrial protein aggregation stimulates a cytosolic molecular chaperone response
The researchers then compared the transcriptomic changes that occurred in response to pRIP1 overexpression and a genetic mutant of protein import, TIM23 presequence translocase, pam16-3. Both alterations led to the downregulation of oxidative phosphorylation genes and an upregulation of chaperone genes. Mitochondrial dysfunction was induced chemically using carbonyl cyanide m chlorophenyl hydrazine (CCCP), a mitochondrial oxidative phosphorylation uncoupler. This led to observable changes in multiple chaperone proteins, including Hsp42 and Hsp104. This upregulation was then confirmed in multiple other established mitochondrial import mutants. FLAG-tagged metastable mitochondrial proteins and GFP-labelled Hsp42, were used to follow the co-localization of Hsp42 with the proteins. A substantial accumulation of pRip1 in the cytosol was observed and co-localized with Hsp42. To test if these chaperones are responsible for preventing aggregation, the researchers deleted Hsp104 in cells. They subsequently observed an increased accumulation of pRip1 upon CCCP treatment. Therefore, Hsp42 and Hsp104 appear to play a role in limiting mitochondrial precursor protein aggregation in the cytosol.
3.) Mitochondrial failure impairs cellular protein homeostasis
In the final section of the paper, the authors asked if the presence of aggregation-prone mitochondrial precursor proteins could stimulate the accumulation of other mitochondrial precursor proteins. They found that the overproduction of Atp2 and Cox8 led to the accumulation of pRip1 and pSod2. This cytosolic co-aggregation may explain why Atp2, Cox8, and Atp20 showed the most severe impact on the lethality of cells. Following this, they tested for a snowball-like effect where aggregation of mitochondrial proteins led to aggregation of other non-mitochondrial proteins. Using a yeast model expressing mutant a-synuclein (a-syn), they observed an increased number of a-syn aggregates in response to defective mitochondrial import. This increased level of a-syn aggregation corresponded with a higher level of pRip1 aggregation, indicating that mitochondrial precursor aggregation led to the increased aggregation of non-mitochondrial proteins. Lastly, the research team moved to a C. elegans model to test whether this precursor aggregation compromised organismal protein homeostasis. Using RNAi silencing of dnj-21, which stimulated a similar import defect to the one observed in yeast pam16-3, aggregation of fluorescently labelled proteins was observed. They also tested if the link between mitochondrial dysfunction and non-mitochondrial protein aggregation was a-syn specific. To do this, they silenced dnj-21 in worms carrying amyloid beta (Aβ). Aβ aggregates increased following dnj-21 silencing. There were no alterations in the expression level of Aβ peptides, thus confirming that the defective mitochondrial import was responsible for increased aggregation.
What I like about this preprint:
This preprint addresses a critical knowledge gap in the understanding of neurodegeneration that has long needed addressing. It is now understood that over 30 human neurodegenerative diseases can be classified as proteinopathies7. Despite the understanding that these diseases all have hallmark protein accumulation, aberrant proteostasis within the cell is not well understood in many of these diseases. Importantly, this research shows a conserved mechanism of protein import dysfunction between two model organisms. Showing this pathway’s ability to regulate protein aggregation in multiple organisms makes pursuing it in future studies much more attractive. Developing an understanding of the mechanisms that regulate proteostasis may help uncover common developmental hallmarks of neurodegenerative diseases, leading to therapeutic targets for multiple disorders.
Questions to the authors:
1.) It appears that your findings support a role for the molecular chaperones as a first line of defense against aberrant protein aggregation in the cytosol. Do you think that these HSPs provide a potential therapeutic target? Especially in the early stages of proteinopathy progression, it seems that this would alleviate some cellular stress.
2.) Do you think there are direct protein-protein interactions between the aggregating mitochondrial proteins and the proteins related to neurodegenerative diseases (i.e., a-syn and Aβ)? Or is the aggregation of one protein overloading the cell’s stress response and chaperones, thus taking away from the cell’s ability to deal with other potentially detrimental aggregates?
References:
- Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol. 2019;20(5):267-284. doi:10.1038/s41580-018-0092-0
- Boos F, Kramer L, Groh C, et al. Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme. Nat Cell Biol. 2019;21(4):442-451. doi:10.1038/s41556-019 0294-5
- Cenini G, Rub C, Bruderek M, Voos W. Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process. Mol Biol Cell. 2016;27(21):3257-3272. doi:10.1091/mbc.E16-05-0313
- Vicario M, Cieri D, Brini M, Cali T. The close encounter between alpha-synuclein and mitochondria. Front Neurosci. 2018;12(JUN):1-13. doi:10.3389/fnins.2018.00388
- Ciryam P, Kundra R, Freer R, Morimoto RI, Dobson CM, Vendruscolo M. A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation. Proc Natl Acad Sci U S A. 2016;113(17):4753-4758. doi:10.1073/pnas.1516604113
- Kundra R, Ciryam P, Morimoto RI, Dobson CM, Vendruscolo M. Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease. Proc Natl Acad Sci U S A. 2017;114(28):E5703-E5711. doi:10.1073/pnas.1618417114
- Golde TE, Borchelt DR, Giasson BI, Lewis J. Thinking laterally about neurodegenerative proteinopathies. J Clin Invest. 2013;123(5):1847-1855. doi:10.1172/JCI66029
doi: https://doi.org/10.1242/prelights.28964
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