Temporal landscape of mitochondrial proteostasis governed by the UPR mt

Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPR mt ) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPR mt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPR mt ’s role in maintaining proteostasis during stress. We find essential roles for the UPR mt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPR mt . Transcriptome analyses together with MitoPQ reveal that UPR mt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPR mt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPR mt failed. Collectively, this study defines the network of proteostasis mediated by the UPR mt and highlights the value of functional proteomics in decoding stressed proteomes. Functional proteomics reveals how the UPR mt safeguards mitochondrial proteostasis and metabolism during stress.