Trends in Cell Biology
ReviewHow the Mitoprotein-Induced Stress Response Safeguards the Cytosol: A Unified View
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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