Trends in Cell Biology
Volume 30, Issue 3, March 2020, Pages 241-254
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Review
How the Mitoprotein-Induced Stress Response Safeguards the Cytosol: A Unified View

https://doi.org/10.1016/j.tcb.2019.12.003Get rights and content

Highlights

  • Owing to their post-translational mode of import, mitochondrial precursor proteins represent a significant challenge to the cells’ ability to maintain cytosolic proteostasis, particularly when the amount of cytosolic precursors exceeds the import capacity of mitochondria.

  • Mitoprotein-induced stress elicits a complex regulatory network that: (i) removes stalled precursors from the mitochondrial surface, (ii) slows down the synthesis of mitochondrial proteins, and (iii) increases the levels of chaperones and proteases and attenuates cytosolic translation.

  • Seemingly disparate reactions to mitochondrial stress are integrated into a general mitoprotein-induced stress response that couples ‘mitochondria-centric’ adaptations with general stress programs such as the heat shock response.

Mitochondrial and cytosolic proteostasis are of central relevance for cellular stress resistance and organismal health. Recently, a number of individual cellular programs were described that counter the fatal consequences of mitochondrial dysfunction. These programs remove arrested import intermediates from mitochondrial protein translocases, stabilize protein homeostasis within mitochondria, and, in particular, increase the levels and activity of chaperones and the proteasome system in the cytosol. Here, we describe the different responses to mitochondrial perturbation and propose to unify the seemingly distinct mitochondrial-cytosolic quality control mechanisms into a single network, the mitoprotein-induced stress response. This holistic view places mitochondrial biogenesis at a central position of the cellular proteostasis network, emphasizing the importance of mitochondrial protein import processes for development, reproduction, and ageing.

Section snippets

The Emerging Role of Mitochondria in the Regulation of Cellular and Organismal Protein Homeostasis

Organization of the subcellular environment into distinct, membrane-bound organelles is a key feature of eukaryotic cells. While this allows cells to operate efficiently through the creation of functionally specialized environments, the spatial and temporal separation of protein synthesis, folding, and degradation also presents a significant challenge to the cells’ ability to maintain protein homeostasis (proteostasis).

In order to counteract proteostasis imbalances within compartments, cells

Mitochondrial Protein Import Is the Nexus between Mitochondrial and Cytosolic Proteostasis

Mitochondria are responsible for the bulk of cellular ATP production and are classically referred to as the ‘powerhouses’ of the cell. Interestingly, a growing number of studies have connected mitochondrial function with susceptibility to, and protection against, cytosolic protein aggregation [7., 8., 9., 10., 11., 12., 13.]. Impaired cell function as a consequence of mitochondrial dysfunction was initially attributed to changes in the levels of ATP or reactive oxygen species (ROS); however,

Consequences of Impaired Mitochondrial Protein Import

If mitochondrial protein import is defective, cells face two major challenges. On the one hand, the lack of protein supply leads to proteome imbalances inside mitochondria, comparable with consequences of defects in the expression of the mitochondrial genome [40]. On the other hand, import defects result in the accumulation of precursor proteins in the cytosol and challenge proteostasis outside mitochondria.

It has been estimated that under normal basal conditions, around 5% of nascent ER

Cellular Reactions to Compromised Mitochondrial Protein Import

Cells use a repertoire of means to prevent an overload of mitochondrial protein import and to counteract the consequences of import failure for both mitochondria and the cytosol. Initially described as individual phenomena, numerous studies have revealed that cells safeguard mitochondrial protein import and restore mitochondrial/cytosolic homeostasis by: (i) unclogging jammed translocases and removing accumulating precursor proteins from the mitochondrial surface [19,20]; (ii) adjusting the

Conservation of the Mitoprotein-Induced Stress Response

Although well-described in yeast, the regulatory basis and composition of the mitoprotein-induced stress response in metazoans is less well understood. However, available evidence suggests that analogous mechanisms to those observed in fungi are present in animals. For example, the targeting of misfolding-prone substrates to mitochondria, genetic and chemical inhibition of respiration, and perturbation of mitochondrial HSP70 have all been reported to increase the expression of HSF1 target genes

Concluding Remarks

Over the past 5 years, it has become increasingly evident that cellular stress resistance and organismal health are highly dependent on connections between mitochondrial and cytosolic proteostasis. While not all connections and causalities are understood (see Outstanding Questions), two major paradigms have emerged: first, the proteostasis and quality control programs from different subcellular compartments are distinct, but do not act in isolation from each other. Second, many seemingly

Acknowledgments

We thank Katharina Knöringer, Lena Krämer, Carina Groh, and Jana Friedl for helpful discussions and valuable comments on the manuscript. Authors were supported by funding from the Deutsche Forschungsgemeinschaft (DIP MitoBalance, IRTG1830 and the SPP1710 to J.M.H.), the Forschungsinitiative Rheinland Pfalz BioComp (to J.M.H.), the Joachim Herz Stiftung (to F.B.), a BBSRC David Phillips Fellowship (to J.L.), an AMS Springboard Award (to J.L.), and a Wellcome Trust Institutional Strategic Support

Glossary

Endoplasmic reticulum-associated protein degradation (ERAD)
mediates the removal of proteins from the ER lumen or membrane by proteasomal degradation.
Heat shock response (HSR)
signaling pathway that is induced by the accumulation of unfolded or misfolded proteins in the cytosol and/or nucleus. The HSR is triggered by exposure to high temperature but can be induced by any conditions that promote protein misfolding.
Mitochondrial compromised protein import response (mitoCPR)
extraction system to

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