Aggregates are aberrant, non-functional forms of protein that often build up in cells in response to stress. Organelles called mitochondria have now been found to be active players in the clearance of these protein aggregates. See Letter p.443
Organelles called mitochondria are key metabolic centres, and are derived from bacterial ancestors that were taken up by nucleus-bearing cells. During evolution, the bacterium-derived genes were exported to the nucleus, and now almost all of the proteins they encode must be transported back into mitochondria from the cell's cytosolic fluid. A sophisticated complement of transport machinery has evolved to recognize and translocate immature mitochondrial proteins into mitochondria1,2. On page 443, Ruan et al.3 report an unexpected role for this translocation in managing a type of cellular waste that forms under conditions of heat stress.
Under stressful conditions, proteins cannot always achieve or maintain structural integrity. The resulting unfolded or misfolded proteins do not perform their normal functions and often clump together into high-molecular-weight deposits called aggregates, posing a threat to cellular homeostasis4,5,6,7. Cells use several mechanisms to deal with protein aggregates — for instance, digesting them inside vesicles in a process called autophagy, or degrading them in a protein complex known as the proteasome. Dividing yeast cells also use another strategy, asymmetrically depositing protein aggregates into a mother cell to ensure that a daughter remains healthy8,9.
Ruan et al. investigated waste management of aggregates in yeast. First, they identified a set of proteins that formed aggregates when subjected to heat stress. Under these conditions, the aggregating proteins interacted with the proteins Tom40 and Tom70. These two proteins are part of a complex dubbed translocase of the outer membrane, which acts as a main entry gate to the mitochondria.
The researchers discovered that the aggregating proteins became associated with the mitochondrial surface (Fig. 1). Surprisingly, a subpopulation was gradually sorted from the other proteins and reached the organelle's matrix, which lies inside a second, inner membrane. However, the authors did not investigate why some proteins are sorted and what distinguishes this population from unimported proteins. The import of aggregating proteins through a translocase of the inner membrane required an electrochemical potential across the inner mitochondrial membrane, similar to the import of immature mitochondrial proteins1,2. This observation, together with the ability of aggregates to interact with the outer-membrane translocase, indicates that aggregating proteins and mitochondrial proteins may share the same mitochondrial import pathway.
What do mitochondria do with non-mitochondrial, functionally useless proteins that have a tendency to aggregate? The paper provides a surprising explanation: cells use mitochondria as a means of disposing of these proteins. Thus, in addition to importing proteins during their biogenesis, mitochondria act as a transient deposit for cellular waste.
Proteins must be in an unfolded state to be imported. Ruan et al. found that a chaperone protein called Hsp104, which is involved in disaggregation, is required for the efficient mitochondrial uptake of aggregating proteins. By contrast, defects in the activity of another cytosolic chaperone protein, Hsp70, seem to promote the import of aggregating proteins. Thus, the study provides intriguing insights into the mechanisms that underlie the role of cytosolic chaperones in coupling mitochondrion-linked aggregates to mitochondrial translocase activity. Chaperones are distributed throughout the cytosol, and it will be interesting to understand the spatial control of this coupling process.
The researchers next identified the mitochondrial matrix enzyme Pim1 as a factor involved in the degradation of imported aggregate proteins. Pim1 is a protease, which mediates protein breakdown. However, it is possible that other factors also contribute to mitochondrion-linked aggregate clearance. One candidate is the proteasome, which could potentially clear aggregating proteins on the mitochondrial surface — but the authors excluded a role for this system.
Another possibility is that disaggregated proteins exhaust the capacity of the translocation machinery, leading to clogging. This could result in the activation of alternative clearance mechanisms involving as-yet-unknown proteases or other actions at the organelle level, such as separation and clearance of aggregate-marked mitochondria along with their entire protein content. Clearance routes that dispose of aggregating proteins by moving them back out of mitochondria should not be excluded and could involve a vesicle-based mechanism10. Finally, several mechanisms might act in concert to ensure that cells contain healthy mitochondria that are unburdened by aggregates.
Of course, questions remain, and are centred on two major areas: mechanisms of aggregate sorting and clearance, and their consequences for physiology and pathology. Mitochondrial proteins contain specific structural signals that are deciphered by mitochondrial translocases to lead the proteins to the correct location in the organelle. How are aggregating non-mitochondrial proteins (which lack the normal signals required for mitochondrial targeting) bound to mitochondria and sorted by mitochondrial translocases? Although the pathway for importing aggregating proteins seems to rely on general mitochondrial import mechanisms, it will be interesting to see whether any unique alterations, including unknown components, are specifically engaged in the mitochondrial sorting of aggregating proteins.
From the perspective of cellular physiology and pathological processes, the most exciting questions are about the functionality of mitochondria that are busy disposing of aggregates, their role in maintaining cellular-protein homeostasis and how they affect the failure of this process in disease. Ruan and colleagues provide evidence that mitochondrial aggregate disposal is active not only during heat stress but also under a broader range of physiological conditions. In a final set of experiments, they observed a similar phenomenon in human cells. Together, these data indicate that the mechanism could be widespread and evolutionarily conserved. Defects in mitochondrial function and an inability to deal with aberrant proteins are common features of age-related and neurodegenerative diseases in humans. Perhaps defects in mitochondrial aggregate clearance are a part of the mechanisms that trigger and accompany cellular degeneration during disease.
The mitochondrial pathway of aggregate clearance is likely to form an important addition to our knowledge of the mechanisms involved in maintaining cellular-protein homeostasis. Interestingly, the efficiency of mitochondrial protein import affects the ability of cells to clear proteins in the cytosol11. Ruan and colleagues' work provides another fascinating example of the crosstalk between the mitochondrial import machinery and cytosolic-protein homeostasis. It is becoming increasingly clear that maintaining a productive dialogue between cellular compartments is a crucial task — one that we are just beginning to understand.Footnote 1
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Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2018)
Russian Journal of Genetics (2018)
Advances in Colloid and Interface Science (2017)