Folding the Mitochondrial UPR into the Integrated Stress Response

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.