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.