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 is activated. The UPR 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 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 in the invertebrate model organism and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPR in worms, flies and mice, and how UPR activation in specific tissues affects organismal metabolism and longevity.