Mitochondria Retrograde Signaling and the UPR mt: Where Are We in Mammals?

Abstract

Mitochondrial unfolded protein response is a form of retrograde signaling that contributes to ensuring the maintenance of quality control of mitochondria, allowing functional integrity of the mitochondrial proteome. When misfolded proteins or unassembled complexes accumulate beyond the folding capacity, it leads to alteration of proteostasis, damages, and organelle/cell dysfunction. Extensively studied for the ER, it was recently reported that this kind of signaling for mitochondrion would also be able to communicate with the nucleus in response to impaired proteostasis. The mitochondrial unfolded protein response (UPR(mt)) is activated in response to different types and levels of stress, especially in conditions where unfolded or misfolded mitochondrial proteins accumulate and aggregate. A specific UPR(mt) could thus be initiated to boost folding and degradation capacity in response to unfolded and aggregated protein accumulation. Although first described in mammals, the UPR(mt) was mainly studied in Caenorhabditis elegans, and accumulating evidence suggests that mechanisms triggered in response to a UPR(mt) might be different in C. elegans and mammals. In this review, we discuss and integrate recent data from the literature to address whether the UPR(mt) is relevant to mitochondrial homeostasis in mammals and to analyze the putative role of integrated stress response (ISR) activation in response to the inhibition of mtDNA expression and/or accumulation of mitochondrial mis/unfolded proteins.

Keywords: cell signaling; gene expression; mitochondria; unfolded protein response.

Figure 1

The UPR^mt models in mammalians. Two major independent models of UPR^mt have been described. When unfolded proteins accumulate in the mitochondrial matrix, they are first cleaved by ClpP proteases. Peptides exit mitochondria by unknown mechanisms and trigger a signaling pathway, leading to the activation of c-Jun N-terminal kinase (JNK) and PKR, which phosphorylate as c-Jun (part of AP-1 transcription factor) and eIF2α, respectively. The phosphorylation of eIF2α can also be mediated by GCN2 in response to mitochondrial translation inhibition (not illustrated), and it turns on the integrated stress response (see Figure 2). PKR could also activate JNK. The activation of c-Jun triggers CHOP-10 expression. In turn, the transcription factor regulates the expression of stress-resolving genes such as mitochondrial proteases and chaperones (left side of the chart). When unfolded proteins accumulate in the inter-membrane space, the UPR^mt is mediated by the activation of ERα, triggered by an AKT-dependent phosphorylation. The activation of AKT would then be mediated by oxidative stress, as inhibited by N-acetylcysteine (NAC). Mitochondrial stress resolves by an increase in the expression of HTRA2/Omi protease and enhanced proteasome activity, while the biogenesis of mitochondria is enhanced and under the control of NRF1, a target gene of ERα. The highlighted acronyms represent genes for which an endogenous differential expression (RT-qPCR or Western blot analysis) in response to UPR^mt has been experimentally demonstrated to be dependent on CHOP-10; this is in addition to analysis using reporter constructs. The non-highlighted genes refer to genes controlled by CHOP-10 in response to a UPR^mt, but only demonstrated using reporter constructs.

Figure 2

Hypothetical model for stress response to mitochondrial dysfunction. In response to various stresses, several kinases, such as HRI, PKR, PERK, and GCN2, are activated and converge to phosphorylate the translation initiation factor eIF2α. In turn, the phosphorylation of eIF2α has at least two consequences. While the cytosolic translation is globally attenuated as it inhibits CAP-dependent translation, mRNAs containing a uORF are preferentially translated, such as the transcription factor ATF4, which controls the expression of CHOP-10. The profit of this GCN2-eIF2α-ATF4 pathway might be stress attenuation gained by relieving the load of proteins imported into the mitochondria and increasing the expression of integrated stress responsive genes.