. Cytosolic proteostasis through importing of misfolded proteins into mitochondria. Nature. 2017 Mar 16;543(7645):443-446. Epub 2017 Mar 1 PubMed.

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  1. Loss of proteostasis occurs in neurodegenerative diseases in general, and in Alzheimer’s in particular. This phenomenon, I think, is trying to tell us something important about neurodegenerative disease mechanisms. One possibility is that proteins aggregate, and that this directly causes neurodysfunction and neurodegeneration. Another is that dysfunctional, stressed, or dying cells develop and accumulate protein aggregates. A feed forward loop in which dysfunction begets aggregation which begets more dysfunction could also occur.

    The beauty of this study is that it provides fundamental new information on how cells deal with intracellular protein aggregations. Here, Ruan et al. show that mitochondria themselves play a role in maintaining intracellular proteostasis, at least in yeast, but probably in mammalian cells as well. Who would have guessed that mitochondria are central players in a chaperone-mediated process through which parts of aggregated peptides are shuttled piecemeal into mitochondria, and then degraded by mitochondrial peptidases?

    I think this study has potential Alzheimer’s implications. Over the past decade multiple investigators have shown aggregable proteins, including Aβ, appear at or within the mitochondrion, raising the possibility that these proteins interfere with normal mitochondrial function. Alternatively these proteins may even potentially serve a physiologically relevant role that involves modifications of mitochondria function.

    In defining this phenomenon the experimental design really only looked at the ability of aggregated proteins to access mitochondria. Its goal was not to address the question of why this phenomenon evolved in the first place. At this stage of the game this is fine. Plus, I loved the last sentence, in which the authors speculate that maybe a primary mitochondrial functional decline, such as occurs in aging, could through this phenomenon go on to have a protean impact on proteostasis. It will be interesting to see what spin-offs arise from this new observation.

    View all comments by Russell Swerdlow
  2. This is a very well done study of broad interest to scientists interested in the link between misfolded proteins and neurodegeneration. There is a great deal of evidence that mitochondria play an important role in the pathogenesis of neurodegenerative diseases, and proteins such as amyloid and α-synuclein are found either within mitochondria or in association with mitochondria-associated ER membranes (MAMs). The present paper demonstrates that aggregation-prone proteins can enter the mitochondria, where they undergo degradation. Increased import causes mitochondrial stress, which may contribute neurodegeneration.

    View all comments by M. Flint Beal
  3. Ruan and colleagues present an impressive set of data indicating an important role for mitochondria as scavengers of aggregated proteins. They term this process MAGIC, and of course if you put a new name, especially such a tantalizing one, on a cellular process, you’re onto something potentially very importan ... MAGIC is regulated, through the influence of Hsp104, by mitochondrial import, and by mitochondrial proteases, with a major role suggested for Pim1. Conceptually, this is very exciting, as it challenges our view of the mitochondria as basically energy-producing organelles, and suggests that they may have a considerable and specific role in removing aggregated proteins, something previously associated with other cellular organelles and processes, such as macroautophagy, the proteasome, and ERAD. These findings thus touch on fundamental aspects of cell biology.

    Given the importance of protein aggregation in neurodegenerative diseases at large, and the therapeutic efforts underway to enhance endogenous clearance mechanisms to combat such protein aggregation, this discovery may provide a new therapeutic target for neurodegeneration. The authors use an impressive array of cell biology and biochemical assays mainly in yeast cells. It is important that, under the admittedly somewhat artificial conditions of heat shock, MAGIC was a major pathway for aggregate clearance, compared to other established processes. However, generalization of the importance of this process to mammalian cells, in particular in an in vivo situation, remains to be demonstrated. A small set of experiments in mammalian cells does suggest, however, that MAGIC may be operating in such systems as well, but its comparative importance to other protein degradation systems and its role in endogenous aggregated protein turnover were not assessed. The exact molecular pathway of recognition and uptake of aggregated proteins into mitochondria also requires further elucidation.  

    View all comments by Leonidas Stefanis
  4. Mitochondrial dysfunction is increasingly being investigated as a pathophysiological contributor to neurodegenerative diseases including Alzheimer’s disease (AD). Several mitochondrial cellular processes are involved in the biogenesis, folding, trafficking, and clearance of proteins that maintain cytosolic proteostasis. This paper describes the results of biochemical studies in yeast to investigate the import of protein aggregates into mitochondria. Notably, in response to heat shock, protein aggregates form, interact with both cytosolic and mitochondrial proteins, and are imported into mitochondria. Translocase of the outer mitochondrial membrane proteins (Tomm70 and Tomm40), which transport peptides and proteins into the mitochondria, were found to co-purify with the protein aggregates, evidence for interaction. Defects in a cytosolic heat shock protein (Hsp70) were found to accelerate the import of misfolded proteins into the mitochondria and in turn increase mitochondrial stress.

    To conceptualize the results, the authors develop the concept of mitochondria as guardian in cytosol (MAGIC), in other words, the mitochondria has a specific role in facilitating protein disaggregation in the cytosol by removing and transporting dissociated proteins into the mitochondria in response to stress. As a consequence, the dissociated proteins could accumulate in mitochondria and have an impact on development of disease. Genetic and biochemical data have supported a role for Tomm40 in late-onset neurodegenerative diseases including AD; the present study provides specific data on cellular interactions that may offer a mechanistic interpretation for this role. The results discussed in the paper and the approach are innovative in terms of stimulating new thinking about the underlying neurobiology of AD, specifically the involvement of mitochondria and outer membrane proteins including Tomm40. 

    View all comments by Michael Lutz
  5. Ruan et al. reported a novel mitochondrial function in yeast in preventing protein aggregation. The authors demonstrated that heat shock stress can induce extensive protein aggregates in yeast and that normal mitochondria play an important role in eliminating these unhealthy aggregates. This process depends on HSP104, TIM23, PIM1, as well as an intact mitochondrial membrane potential. Although there is significant distinction between yeast and mammalian cell mitochondria, the mitochondria as guardian in cytosol (MAGIC) pathway will also be expected in the human tissues, besides numerous recently discovered new functions for mitochondria.

    Further studies to identify similar pathways in mammalian cells or neurons will be important steps in discovering therapy for neurodegenerative disorders. Our previous work had shown an important role of mitochondrial proteases in processing amyloid peptide generated in the cytosol, which can be an example of MAGIC pathway in neuronal cells. Presequenceprotease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. We have demonstrated that PreP was significantly reduced in AD brains and in transgenic Alzheimer’s disease mouse models that overexpress human Aβ (Alikhani et al., 2011). Importantly, increased neuronal PreP activity attenuated cerebral and mitochondrial pools of Aβ, and rescued mitochondrial and synaptic function, as well as learning and memory (Fang et al., 2015). These results suggest that PreP functions as a peptide scavenger, clearing mitochondria of Aβ, and thereby protecting mitochondria against pathogenic peptide intruders. We also unexpectedly observed that increased expression of PreP not only degrades mitochondrial Aβ but also affects total brain Aβ levels, suggesting that mitochondrial Aβ is not just a “spilling over” from cellular aggregation and that PreP also has an important regulating effect on total brain Aβ levels. Given that exogenous or intracellular Aβ is capable of direct transport into mitochondria via mitochondrial channel proteins such as TOMM40, the receptor for advanced glycation end product (RAGE), or by an unknown mechanism, the mitochondrial pool of Aβ may undergo dynamic changes in different intracellular compartments, contributing to the balance of intracellular/extracellular Aβ accumulation. 

    References:

    . Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria. J Alzheimers Dis. 2011 Jan 1;27(1):75-87. PubMed.

    . Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model. Hum Mol Genet. 2015 Sep 15;24(18):5198-210. Epub 2015 Jun 29 PubMed.

    View all comments by Shirley ShiDu Yan

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  1. It’s MAGIC: Yeast Mitochondria Make Cytosolic Protein Aggregates Disappear