Figure 1. ATFS-1 represses OxPhos and TCA cycle gene expression while inducing mitochondrial proteostasis and glycolysis genes during mitochondrial dysfunction.

(A) Beause ATFS-1 contains a mitochondrial targeting sequence (MTS), it is efficiently imported into mitochondria and degraded. However during mitochondrial stress, import efficiency of ATFS-1 is reduced causing a percentage of it to traffic to the nucleus via its nuclear localization sequence (NLS) where it regulates the UPR^mt.

(B) In the nucleus, ATFS-1 regulates expression of over 400 genes including the induction of mitochondrial proteostasis genes (chaperones, proteases) as well as glyolysis and innate immune genes. Simultaneously, ATFS-1 limits the accumulation of the highly expressed TCA cycle and oxidative phosphorylation (OxPhos) transcripts. During stress, a percentage of ATFS-1 is also stabilized within mitochondria where it limits the accumulation of mtDNA-encoded OxPhos transcripts.

(C) UPR^mt activation results in a reduction of nuclear and mtDNA-encoded OxPhos transcripts to promote stoichiometric complex assembly and reduce the substrate burden on the overwhelmed proteostasis environment in stressed mitochondria. Together, ATFS-1 promotes the regeneration of OxPhos complexes while increasing glycolytic capacity to maintain ATP levels.