A cytosolic surveillance mechanism activates the mitochondrial UPR
F.X. Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch
Abstract
Abstract The mitochondrial unfolded protein response (UPR mt ) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis 1,2 . Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPR mt (refs. 3,4 ). Here, we show that UPR mt signalling is driven by the release of two individual signals in the cytosol—mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPR mt ; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPR mt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPR mt . These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPR mt signalling in human cells.