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.