NEWS & VIEWS

doi:10.1038/nature14644

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).
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

C E LL B IO LO GY

Surviving import
failure
Two studies reveal that dysfunction in organelles called mitochondria causes the
toxic accumulation of mitochondrial proteins in the cells cytosolic fluid, and
identify ways in which damage is mitigated.
C O L E M . H AY N E S

n 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 published on Natures
website 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 cells energy. Defects in mitochondrial function often arise with ageing,
or in diseases associated with neuromuscular
degeneration, including Parkinsons 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 used
an unbiased screening approach to identify
40genes 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 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

b
Ribosome

Cytosol
Protein
synthesis
Import
Mitochondria
Mitochondrial
protein
Proteasome

Figure 1 | Effects of decreased mitochondrial-protein import. a, Around 1,000 of the proteins that
are synthesized by ribosomes in the cells 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.
| NAT U R E | 1

2015 Macmillan Publishers Limited. All rights reserved

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

2 | NAT U R E |

2015 Macmillan Publishers Limited. All rights reserved

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.
Cole M. Haynes is at the Cell Biology
Program, Memorial Sloan Kettering Cancer
Center, New York, New York 10065, USA.
e-mail: haynesc@mskcc.org
1. Wang, X. & Chen, X. J. Nature http://dx.doi.
org/10.1038/nature14859 (2015).
2. Wrobel, L. et al. Nature http://dx.doi.org/10.1038/
nature14951 (2015).
3. Matsuo, Y. et al. Nature 505, 112116 (2014).
4. Le Tallec, B. et al. Mol. Cell 27, 660674 (2007).
5. Sammons, M. A., Samir, P. & Link, A. J. Biochem.
Biophys. Res. Commun. 406, 1319 (2011).
6. Akerfelt, M., Morimoto, R. I. & Sistonen, L. Nature
Rev. Mol. Cell Biol. 11, 545555 (2010).
7. Nargund, A. M., Pellegrino, M. W., Fiorese, C. J.,
Baker, B. M. & Haynes, C. M. Science 337, 587590
(2012).
8. Narendra, D. P. et al. PLoS Biol. 8, e1000298 (2010).
9. Johnson, S. C. et al. Science 342, 15241528 (2013).