The mitochondrial unfolded protein response: acting near and far

Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPR^mt is activated. The UPR^mt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPR^mt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPR^mt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPR^mt in worms, flies and mice, and how UPR^mt activation in specific tissues affects organismal metabolism and longevity.