Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.

Abstract

The mitochondrial unfolded protein response (UPR^mt), which promotes mitochondrial biogenesis and proteostasis, is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, using an RNAi suppressor screen, we find that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and developmental rate in atfs-1(null) worms. NHR-180 levels increase and become more nuclear-localized during mitochondrial dysfunction, inducing transcription of genes required for protein synthesis on cytosolic and mitochondrial ribosomes. The NHR-180 ligand-binding domain interacts with AMP, suggesting that NHR-180 may link cellular energy status to protein synthesis during mitochondrial stress. However, NHR-180-dependent activity is associated with exacerbated mitochondrial dysfunction. Consistent with these findings, inhibition of the S6 kinase homolog RSKS-1 increases mitochondrial function in atfs-1(null) worms. S6 kinase inhibition also increases respiration and mitochondrial DNA (mtDNA) content in mammalian ATF5-knockout cells and oxidative phosphorylation (OXPHOS)-deficient models.