Cell biology

Surviving import failure

Two studies reveal that dysfunction in organelles called mitochondria causes the toxic accumulation of mitochondrial proteins in the cell's cytosolic fluid, and identify ways in which damage is mitigated. See Letters p.481 & p.485

In an endosymbiotic event that occurred more than one billion years ago, a bacterium was engulfed by a cell, and eventually became an organelle — the mitochondrion. Over time, most of the roughly 1,000 genes that encode mitochondrial proteins were transferred from mitochondria to the nucleus, and are now translated into proteins in the intracellular fluid known as the cytosol. A crucial import mechanism then ensures that these proteins end up in the appropriate locations within mitochondria. Now, two complementary studies1,2 in this issue provide insight into the consequences of inefficient import of mitochondrial proteins — their accumulation in the cytosol — and demonstrate that the cell undergoes several adaptive responses to mitigate the toxicity caused by such accumulation.

Mitochondria not only act as signalling hubs, but are also responsible for generating most of the cell's energy. Defects in mitochondrial function often arise with ageing, or in diseases associated with neuromuscular degeneration, including Parkinson's disease and amyotrophic lateral sclerosis. In these settings, mitochondrial dysfunction is thought to contribute to cell dysfunction and ultimately death, either by causing abnormal energy production or by initiating a cell-death program known as apoptosis. But could cell death that is related to mitochondrial dysfunction instead arise owing to an unknown or unanticipated effect on other essential cellular compartments or activities?

In the first study, Wang and Chen1 (page 481) used an unbiased screening approach to identify 40 genes that prevent cell death when overexpressed in cells harbouring damaged mitochondria. None of the proteins encoded by these genes are mitochondrial. Instead, almost all reside in the cytosol, suggesting that mitochondrial dysfunction may alter essential cytosolic functions — a previously unknown effect. Indeed, some of the identified proteins are known to decrease the rate of cytosolic protein synthesis, or to promote protein degradation in the cytosol.

Wrobel and colleagues2 (page 485) took an alternative approach in the second study, analysing all the RNA transcripts and proteins that are altered in cells in which mitochondrial import is impaired. Strikingly, expression and production of many of the genes and proteins required for protein synthesis were reduced, as was overall protein synthesis. Furthermore, the activity of the proteasome (a large complex that degrades proteins in the cytosol) was increased, as were levels of proteasome assembly factors and chaperone proteins3,4.

Both studies demonstrate that mitochondrial precursor proteins accumulate in the cytosol when mitochondrial function is perturbed. Interestingly, the proteins are degraded relatively quickly in the cytosol, compared with when they are imported into mitochondria. Combined with the studies' findings that proteasome activity increases when mitochondria are damaged and has a protective role in this setting, these data suggest that the accumulation of mitochondrial proteins in the cytosol can cause death when mitochondria become dysfunctional.

Most mislocalized proteins will retain their signal sequence — a short peptide that is typically removed after it has helped to guide a protein to its proper location in a mitochondrion — and so might be unable to assemble correctly and adopt a functional conformation. And those proteins that are normally integrated into the mitochondrial membranes are probably prone to forming toxic clumps called aggregates in the aqueous environment of the cytosol. The accumulation of such proteins has the capacity to disrupt or overwhelm essential cytosolic activities that are required for general protein synthesis, folding and assembly. These two studies show how cytosolic adaptations reduce the accumulation of mislocalized proteins, allowing cells to better cope with the consequences of mitochondrial dysfunction (Fig. 1).

Figure 1: Effects of decreased mitochondrial-protein import.

a, Around 1,000 of the proteins that are synthesized by ribosomes in the cell's cytosol are subsequently imported into organelles called mitochondria. b, Mitochondrial dysfunction can impair normal import, leading to toxicity and, if left unchecked, cell death. Two studies1,2 report that cells limit the accumulation of toxic mislocalized mitochondrial proteins in two ways: by reducing protein synthesis and by increasing the activity of proteasomes, structures that degrade the mislocalized proteins.

What are the underlying mechanisms by which cytosolic protein degradation is increased and synthesis is decreased when mitochondrial proteins accumulate in the cytosol? Wang and Chen provide part of the answer, showing that the mitochondrial proteins somehow stabilize cellular protein components that are known3,5 to reduce protein synthesis. Normally, these components are rapidly degraded by proteasomes. But, in the presence of mislocalized mitochondrial proteins, the components avoid degradation, accumulate and reduce protein synthesis.

Both studies reported an increase in proteasome assembly factors, which seems to be independent of transcription. But the mechanism by which levels of these proteins are increased remains unclear. Furthermore, although Wrobel and colleagues reported that changes in the transcription of some genes are required for cells to survive when import is impaired, the way in which this change is regulated remains to be discovered. However, it does not seem to require the signalling mechanisms known6 to be associated with the accumulation of misfolded or aggregated cytosolic proteins, such as the heat-shock response.

Perhaps most importantly, how are the mislocalized mitochondrial proteins identified or detected in the cytosol and directed to the proteasome? Wrobel and colleagues demonstrate that mislocalized proteins are marked with the protein ubiquitin, which tags them for degradation by proteasomes. This indicates that a currently unknown ubiquitin ligase enzyme is involved in their degradation. But the features that indicate that a protein is mislocalized are unclear, because neither the addition of ubiquitin tags nor proteasomal degradation require the mitochondrial signal sequence.

Going forward, it will be interesting to understand how the newly discovered stress response interacts with the two other responses activated by mitochondrial dysfunction and impaired mitochondrial import: a transcriptional response known as the mitochondrial unfolded protein response and the mitophagy pathway. The mitochondrial unfolded protein response is activated to promote survival and mitochondrial repair during mitochondrial dysfunction7. By contrast, the mitophagy pathway uses impaired mitochondrial import to recognize the most severely damaged organelles, and then degrades them to improve cellular fitness8.

Finally, at what point does the toxicity of mislocalized mitochondrial proteins engage apoptotic cell-death pathways? As the authors of both papers suggest, an understanding of this interaction could help to pave the way for the development of treatments for mitochondrial diseases, which until now were thought to arise predominantly from defects in energy production. Perhaps therapeutic strategies to treat mitochondrial diseases should focus on remedying the cytosolic defects caused by mitochondrial-protein accumulation. In support of this suggestion, mice that are treated with a compound that reduces protein synthesis are protected against mitochondrial disease9, providing a cause for optimism about future treatments.Footnote 1


  1. 1.

    See all news & views


  1. 1

    Wang, X. & Chen, X. J. Nature 524, 481–484 (2015).

  2. 2

    Wrobel, L. et al. Nature 524, 485–488 (2015).

  3. 3

    Matsuo, Y. et al. Nature 505, 112–116 (2014).

  4. 4

    Le Tallec, B. et al. Mol. Cell 27, 660–674 (2007).

  5. 5

    Sammons, M. A., Samir, P. & Link, A. J. Biochem. Biophys. Res. Commun. 406, 13–19 (2011).

  6. 6

    Akerfelt, M., Morimoto, R. I. & Sistonen, L. Nature Rev. Mol. Cell Biol. 11, 545–555 (2010).

  7. 7

    Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Science 337, 587–590 (2012).

  8. 8

    Narendra, D. P. et al. PLoS Biol. 8, e1000298 (2010).

  9. 9

    Johnson, S. C. et al. Science 342, 1524–1528 (2013).

Download references

Author information

Correspondence to Cole M. Haynes.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Haynes, C. Surviving import failure. Nature 524, 419–420 (2015). https://doi.org/10.1038/nature14644

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.