Folding the Mitochondrial UPR into the Integrated Stress Response

Abstract

Eukaryotic cells must accurately monitor the integrity of the mitochondrial network to overcome environmental insults and respond to physiological cues. The mitochondrial unfolded protein response (UPR^mt) is a mitochondrial-to-nuclear signaling pathway that maintains mitochondrial proteostasis, mediates signaling between tissues, and regulates organismal aging. Aberrant UPR^mt signaling is associated with a wide spectrum of disorders, including congenital diseases as well as cancers and neurodegenerative diseases. Here, we review recent research into the mechanisms underlying UPR^mt signaling in Caenorhabditis elegans and discuss emerging connections between the UPR^mt signaling and a translational regulation program called the 'integrated stress response'. Further study of the UPR^mt will potentially enable development of new therapeutic strategies for inherited metabolic disorders and diseases of aging.

Keywords: integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling.

Figure 1:

UPR^mt Signaling in Caenorhabditis elegans. In C. elegans, UPR^mt activation is sensitive to the protein import capacity of the mitochondrial network and requires chromatin remodelling. (A) ATFS-1 harbors a mitochondrial targeting sequence (MTS) and a nuclear localization sequence (NLS). The MTS promotes the import and degradation of ATFS-1within healthy mitochondria. However, if mitochondrial import is impaired, which can be caused by OXPHOS dysfunction, or misfolded protein accumulation within the mitochondrial matrix, the NLS of ATFS-1 directs it to the nucleus to activate the UPR^mt. This step requires ATFS-1 desumoylation by ULP-4, which enhances its transcriptional activity. The bZIP protein ZIP-3 also serves as a negative regulator of ATFS-1 activation, functioning in a negative feedback loop. (B) Under basal conditions, LIN-65 resides in the cytosol, DVE-1 and UBL-5 exhibit a diffuse nuclear localization, and the methyltransferase MET-2 is inactive. (C) Mitochondrial stress stimulates MET-2 activity which promotes nuclear import of LIN-65, and together these proteins catalyze H3K9 dimethylation and chromatin condensation, in a manner dependent on CLPP-1. Chromatin condensation, CLPP-1, and SUMO cleavage by ULP-4 activity drive redistribution of DVE-1/UBL-5 to the promoters of UPR^mt responsive genes.

Figure 2.

The Integrated Stress Response (ISR) Is Required for UPR^mt Induction in Mammals. (A) GTP-laden eIF2 binds to methionylated initiator tRNAs (Met-tRNA) to initiate cap-dependent translation. Translation initiation stimulates GTP hydrolysis on eIF2, causing the complex to dissociate. eIF2B then catalyzes exchange of GDP for GTP on eIF2, enabling further rounds of translation initiation. Phosphorylation of eIF2α at S51 (eIF2α-P) converts eIF2 into an inhibitor of eIF2B, which suppresses cap-dependent translation. (B) When eIF2α-P levels are low, monocistronic transcripts are translated, as are the uORFs of polycistronic transcripts. Translation of downstream coding sequences (CDS) is inhibited by uORF translation. (C) High eIF2α-P levels reduce cap-dependent translation. Ribosomes scan past uORFs and instead initiate translation at the downstream CDS. (D) Mitochondrial dysfunction stimulates phosphorylation of eIF2α, though it is unclear which kinases are responsible for the diverse stressors that perturb mitochondrial function. eIF2α phosphorylation enables translation of the transcription factors CHOP, ATF4, and ATF5. ATF5 activity is negatively regulated by mitochondrial import into healthy mitochondria. CHOP, ATF4, and ATF5 stimulate transcription of genes that enable recovery from mitochondrial insults. (E) eIF2α is phosphorylated by four different kinases that are activated by different stimuli. Gcn2 associates with ribosomes and is activated by stalled translation. PERK is an ER membrane protein activated by accumulation of unfolded proteins within the ER lumen. HRI is activated in the absence of heme or binding to DELE1, a mitochondrial protein exported to the cytosol upon cleavage by the stress-activated protease OMA1. PKR activity is stimulated upon binding dsRNA, including those generated in the mitochondrial matrix during transcription.