[2] Mitochondrial electron transport chain mutations that extend the life span of Caenorhabditis elegans (nematode worms) also activate the UPRmt.
[10] Despite their names, the two pathways possess distinct initiating stimuli and signaling mechanisms that regulate the responses.
Mitochondrial dysfunction inhibits this process and allows ATFS-1 to accumulate in the cytosol and enter the nucleus where it can act as a transcription factor.
The MTS on ATFS-1 is predicted by Mitofates[16] to be substantially weaker than most MTSs which would allow it to be sensitive to subtle mitochondrial dysfunction.
In the nucleus, ATFS-1 has a broad transcriptional regulation as it will: attenuate OXPHOS gene expression in both the nucleus and mitochondria, upregulate chaperones and proteases to re-establish mitochondrial proteostasis, increase ROS detoxification, and increase mitochondrial import machinery.
Researchers have identified the SIRT3 axis of UPRmt as a marker to differentiate between metastatic and non-metastatic breast cancer.
[18] As many cancers exhibit a metabolic shift from oxidative phosporylation-depentent energy production to aerobic glycolysis dependent energy production, also known as the Warburg effect, researchers suggest that cancer cells rely on the UPRmt to maintain the mitochondrial integrity.
[15][22] In particular, mitochondrial dysfunction and UPRmt -activation have been linked to intestinal stemness and Paneth cell (dys-)function.