Integrating the UPR into the mitochondrial maintenance network.

Mitochondrial function is central to many different processes in the cell, from oxidative phosphorylation to the synthesis of iron-sulfur clusters. Therefore, mitochondrial dysfunction underlies a diverse array of diseases, from neurodegenerative diseases to cancer. Stress can be communicated to the cytosol and nucleus from the mitochondria through many different signals, and in response the cell can effect everything from transcriptional to post-transcriptional responses to protect the mitochondrial network.

The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.

Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer, and pathogen infections as well as during normal aging. Cells sense and respond to mitochondrial dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPR(mt)), which includes genes that promote mitochondrial protein homeostasis and the recovery of defective organelles [1, 2]. Work in Caenorhabditis elegans has shown that the UPR(mt) is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning.

Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).

Mitochondrial diseases and aging are associated with defects in the oxidative phosphorylation machinery (OXPHOS), which are the only complexes composed of proteins encoded by separate genomes. To better understand genome coordination and OXPHOS recovery during mitochondrial dysfunction, we examined ATFS-1, a transcription factor that regulates mitochondria-to-nuclear communication during the mitochondrial UPR, via ChIP-sequencing. Surprisingly, in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes, ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes.

Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection.

Metazoans identify and eliminate bacterial pathogens in microbe-rich environments such as the intestinal lumen; however, the mechanisms are unclear. Host cells could potentially use intracellular surveillance or stress response programs to detect pathogens that target monitored cellular activities and then initiate innate immune responses. Mitochondrial function is evaluated by monitoring mitochondrial protein import efficiency of the transcription factor ATFS-1, which mediates the mitochondrial unfolded protein response (UPR(mt)).

Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond.

During development and cellular differentiation, tissue- and cell-specific programs mediate mitochondrial biogenesis to meet physiological needs. However, environmental and disease-associated factors can perturb mitochondrial activities, requiring cells to adapt to protect mitochondria and maintain cellular homeostasis. Several mitochondrion-to-nucleus signaling pathways, or retrograde responses, have been described, but the mechanisms by which mitochondrial stress or dysfunction is sensed to coordinate precisely the appropriate response has only recently begun to be understood.

Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.

To better understand the response to mitochondrial dysfunction, we examined the mechanism by which ATFS-1 (activating transcription factor associated with stress-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans. We found that the key point of regulation is the mitochondrial import efficiency of ATFS-1. In addition to a nuclear localization sequence, ATFS-1 has an N-terminal mitochondrial targeting sequence that is essential for UPR(mt) repression.