Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond - PubMed (original) (raw)

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Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond

Cole M Haynes et al. Trends Cell Biol. 2013 Jul.

Abstract

During development and cellular differentiation, tissue- and cell-specific programs mediate mitochondrial biogenesis to meet physiological needs. However, environmental and disease-associated factors can perturb mitochondrial activities, requiring cells to adapt to protect mitochondria and maintain cellular homeostasis. Several mitochondrion-to-nucleus signaling pathways, or retrograde responses, have been described, but the mechanisms by which mitochondrial stress or dysfunction is sensed to coordinate precisely the appropriate response has only recently begun to be understood. Recent studies of the mitochondrial unfolded-protein response (UPRmt) indicate that the cell monitors mitochondrial protein import efficiency as an indicator of mitochondrial function. Here, we review how the cell evaluates mitochondrial function and regulates transcriptional induction of the UPRmt, adapts protein-synthesis rates and activates mitochondrial autophagy to promote mitochondrial function and cell survival during stress.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. The mitochondrial unfolded protein response

An illustration of the signaling mechanism that regulates the induction of the mitochondrial unfolded protein response (UPRmt) as elucidated in C. elegans. The UPRmt is activated during mitochondrial dysfunction or stress resulting in the transcriptional up-regulation of protective genes including mitochondrial chaperones and proteases, those involved in reactive oxygen species (ROS) detoxification, the glycolysis pathway and the mitochondrial protein import machinery. The cell determines mitochondrial function and when it is appropriate to induce the UPRmt by monitoring the mitochondrial protein import efficiency of the transcription factor ATFS-1. In the absence of mitochondrial stress, ATFS-1 is translated and efficiently imported into mitochondria via a mitochondrial targeting sequence (MTS), where ATFS-1 is degraded by the Lon protease. However, during mitochondrial dysfunction, general protein import efficiency is reduced allowing a percentage of ATFS-1 to accumulate in the cytosol. Because ATFS-1 also has a nuclear localization sequence (NLS), it then traffics to the nucleus where it induces the UPRmt. Mitochondrial import efficiency can be impaired or reduced by a number of conditions including mitochondrial chaperone depletion or respiratory chain dysfunction. Additionally, import can be slowed by peptide efflux via the ABC transporter HAF-1, which occurs when the mitochondrial chaperone (green) capacity is exceeded by unfolded proteins (dashed lines); all of which result in UPRmt induction to maintain organelle homeostasis.

Figure 2

Figure 2. The mitochondrial stress-stimulated translation attenuation pathway

A model demonstrating how protein synthesis rates are mediated during mitochondrial stress. Conditions including inhibition of a mitochondrial protease required for respiratory chain quality control and mitochondrial ribosome biogenesis [49, 55], respiratory chain or ATP synthase impairment [48] as well as paraquat treatment [55] result in phosphorylation of the translation initiation factor eIF2α by the kinase GCN2. The subsequent decrease in protein synthesis potentially reduces the burden on the protein folding and respiratory chain complex assembly machinery, thus protecting the protein-folding environment. In addition to reducing global protein synthesis, phosphorylated eIF2α promotes the translation and thus activation of the transcription factor Gcn4p in yeast and Atf4 in mammals, both of which are also protective during mitochondrial stress [48, 49, 74]. It is currently unclear how GCN2 becomes activated or senses mitochondrial dysfunction. But, because GCN2 is known to respond to amino acid deprivation and reactive oxygen species (ROS) and both occur during mitochondrial dysfunction multiple possibilities exist.

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