Sensing the Stress: A Role for the UPRmt and UPRam in the Quality Control of Mitochondria

Abstract

Mitochondria exist as compartmentalized units, surrounded by a selectively permeable double membrane. Within is contained the mitochondrial genome and protein synthesis machinery, required for the synthesis of OXPHOS components and ultimately, ATP production. Despite their physical barrier, mitochondria are tightly integrated into the cellular environment. A constant flow of information must be maintained to and from the mitochondria and the nucleus, to ensure mitochondria are amenable to cell metabolic requirements and also to feedback on their functional state. This review highlights the pathways by which mitochondrial stress is signaled to the nucleus, with a particular focus on the mitochondrial unfolded protein response (UPR^mt) and the unfolded protein response activated by the mistargeting of proteins (UPR^am). Although these pathways were originally discovered to alleviate proteotoxic stress from the accumulation of mitochondrial-targeted proteins that are misfolded or unimported, we review recent findings indicating that the UPR^mt can also sense defects in mitochondrial translation. We further discuss the regulation of OXPHOS assembly and speculate on a possible role for mitochondrial stress pathways in sensing OXPHOS biogenesis.

Keywords: UPR signaling pathways; cytochrome c oxidase; mitochondria; mitochondrial signaling; mitochondrial translation.

Figure 1

Mitochondrial UPR^mt and UPR^am stress response pathways. (A) An accumulation of unfolded proteins inside the mitochondrial matrix triggers the UPR^mt in both mammals and in nematodes. Accumulated proteins are likely processed by the CLPP protease and exported out of the mitochondria, a process that in C.elegans requires the HAF-1 protein. While under physiological conditions ATFS-1 gets imported into mitochondria and constitutively degraded by the AAA⁺-protease LON, exported peptides activate the transcription factor ATFS-1/ATF5 in the cytosol, which translocates to the nucleus to alter the cell's transcriptional program, particularly affecting the transcription of mitochondrial proteins. In C.elegans the UBL-5, LIN-65, and MET-2 proteins also translocate to the nucleus upon UPR^mt activation where they facilitate the binding of transcription factors, ATFS-1 and DVE-1, by chromatin remodeling. A second UPR^mt pathway has also been observed in mammals, whereby UPR^mt activation is sensed by the mitochondrial antiviral signaling protein MAVS by an unknown mechanism, which then triggers the activation of PKR, which in turn phosphorylates the c-Jun N-terminal kinase, JNK. JNK activates c-jun (also by an unknown mechanism), which translocates to the nucleus and, together with AP-1, alters gene transcription. The bZIP transcription factor AFT4 has also been linked to mitochondrial stress response pathways. Localized to the nucleus, ATF4 activates a complex cytoprotective transcriptional program, e.g., by transcriptional control of ATF5. (B) In lower eukaryotes, the accumulation of cytosolic precursors from either a block in mitochondrial import, from mislocalization, or from retrotranslocation out of the mitochondrial intermembrane space, can instigate the UPR^am. This accumulation enhances activity of the Irc25/Poc4 chaperone complex, which is required for assembly of the proteasome. Increased proteasome assembly causes the rapid degradation of accumulated proteins. In an independent stress response mechanism observed in mammals, there is a decrease in cytosolic translation, which is coupled to increased proteasome activity, but the molecular mechanisms underlying this response remain to be defined.

Figure 2

Activation of human UPR^mt by altered mitochondrial translation. Conceivable options to initiate UPR^mt by mitochondrial translation could be OXPHOS biogenesis, mitochondrial miRNA molecules in association with AGO2, PNPase-mediated mRNA processing or translational regulators, such as TACO1 (specific for cytochrome c oxidase (CIV)). Inhibition of mitochondrial translation with different drugs also initiate the UPR^mt. However, actinonin treatment can also provoke an alternative stress response.