UPRmt regulation and output: a stress response mediated by mitochondrial-nuclear communication

Abstract

The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPR^mt), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPR^mt signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways.

Figure 1

Mitochondrial stress response pathways. (A) Recognition and selective degradation of damaged mitochondria is mediated by mitophagy. The kinase PINK1 is stabilized specifically on damaged mitochondria where it recruits the ubiquitin ligase Parkin, which ubiquitinates multiple mitochondrial outer membrane proteins. Ubiquitinated mitochondria are then engulfed by autophagosomes and trafficked to lysosomes where they are degraded. (B) The kinase GCN2, which is activated during mitochondrial dysfunction, mediates translation attenuation during mitochondrial dysfunction by phosphorylating the translation initiation factor eIF2α, which serves to reduce the influx of proteins into mitochondria. (C) Accumulation of mislocalized mitochondrial proteins in the cytosol stimulates proteasome activity to limit the accumulation of the toxic proteins in a pathway dubbed UPR^am (unfolded protein response activated by mistargeted proteins). (D) The UPR^mt is regulated by the competing organelle targeting sequences in the transcription factor ATFS-1. If ATFS-1 is imported into the mitochondrial matrix via the MTS, the transcription factor is degraded. However, if ATFS-1 cannot be imported due to mitochondrial dysfunction, it is trafficked to the nucleus, via the NLS, to activate transcription.

Figure 2

Model by which mitochondrial import efficiency of ATFS-1 and gene products induced by ATFS-1 promote mitochondrial network recovery. (A) The transcription factor ATFS-1 harbors both a mitochondrial targeting sequence (MTS) and a nuclear localization sequence (NLS). ATFS-1 is efficiently imported into healthy mitochondria (green), however, import efficiency is reduced by OXPHOS or mitochondrial proteostasis perturbations that cause mitochondrial dysfunction (yellow, red). If ATFS-1 fails to be imported into mitochondria, it is trafficked to the nucleus where it induces transcription of mitochondrial protective genes including mitochondrial chaperones and proteases, antioxidants as well as mitochondrial protein import components. In turn, mitochondrial import of the protective gene products promotes organelle stabilization and recovery. (B) Relative to the proteins induced during the UPR^mt, the program Mitofates predicts that ATFS-1 has a substantially weaker mitochondrial signal sequence. We hypothesize that a weak MTS allows ATFS-1 to be sensitive to modest mitochondrial dysfunction and translocate to the nucleus. In turn, the strong MTSs in those proteins induced by ATFS-1 can still enter dysfunctional mitochondria with reduced import efficiency to recover function. HSP-6, HSP-60 and DNJ-10 are mitochondrial chaperones, MPPA-1 is a subunit of the mitochondrial presequence processing protease, PPGN-1 is a matrix-localized protease, GLRX-5 is a glutaredoxin that functions in mitochondrial iron-sulfur cluster biogenesis, MRPS-14 is a subunit of the mitochondrial ribosome, TSFM-1 is a mitochondrial translational elongation factor, all of which are induced during mitochondrial dysfunction by ATFS-1. NUO-1, SDHB-1 and ATP-2 are all subunits of the OXPHOS complexes, none of which are activated by the UPR^mt (complexes I, II and V, respectively).

Figure 3

The mammalian UPR^mt is intimately associated with the integrated stress response (ISR). During mitochondrial dysfunction, the translation initiation factor eIF2α is phosphorylated by one of four eIF2α-specific kinases such as GCN2 (also PERK, PKR and HRI). eIF2α phosphorylation results in reduced protein synthesis with a concomitant increase in translation of those mRNAs harboring uORFs in the 5′ UTR. The mRNAs encoding the transcription factors CHOP, ATF4 and ATF5 all harbor multiple uORFs and are preferentially translated during mitochondrial dysfunction (inset). While the precise relationship between these three transcription factors remains to be determined during mitochondrial stress, all three are required for the induction of genes associated with the UPR^mt. Both CHOP and ATF4 induce transcription of Atf5. Like ATFS-1 in C. elegans, ATF5 harbors a mitochondrial targeting sequence potentially allowing it to specifically respond to mitochondrial stress via reduced mitochondrial protein import efficiency.