Temporal landscape of mitochondrial proteostasis governed by the UPR <sup>mt</sup>-Reference-Cited by-同舟云学术

Temporal landscape of mitochondrial proteostasis governed by the UPR ^mt

Published:2023-09-22 Issue:38 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Uoselis Louise¹²³^ORCID,Lindblom Runa¹³^ORCID,Lam Wai Kit¹³^ORCID,Küng Catharina J.¹,Skulsuppaisarn Marvin²^ORCID,Khuu Grace¹³^ORCID,Nguyen Thanh N.¹³^ORCID,Rudler Danielle L.⁴⁵^ORCID,Filipovska Aleksandra⁴⁵^ORCID,Schittenhelm Ralf B.⁶^ORCID,Lazarou Michael¹²³⁷^ORCID

Affiliation:

1. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

2. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.

3. Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA.

4. Harry Perkins Institute of Medical Research and ARC Centre of Excellence in Synthetic Biology, Nedlands, Western Australia, Australia.

5. Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, Nedlands, Western Australia, Australia.

6. Monash Proteomics and Metabolomics Facility, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.

7. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adh8228

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