Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence

• Published in: Nature communications Vol. 13; no. 1; pp. 4462 - 14
• Main Authors: Yue, Sibiao, Wang, Lei, DeMartino, George N., Zhao, FangZhou, Liu, Yi, Sieber, Matthew H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/89; 14/19; 631/136/2434/1706; 631/337/474; 631/80/642/333; 64/24; 82/58; 82/83; 96/10; 96/63; Age; Age related diseases; Cancer; Fatty acids; Gametocytes; Homeostasis; Humanities and Social Sciences; Infertility; Membrane proteins; Metabolism; Mitochondria; multidisciplinary; Oocytes; Outer membrane proteins; Oxidation; Proteasomes; Proteomes; Recruitment; Science; Science (multidisciplinary); Stem cells; Substrates; Ubiquitin; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32206-2

Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and remain dormant as part of their roles in tissue homeostasis, reproduction, and even cancer recurrence. Using a multi-organism approach, we show that dynamic shifts in the ubiquitin proteasome system drive mitochondrial remodeling during cellular quiescence. In contrast to the commonly held view that the ubiquitin-proteasome system (UPS) is primarily regulated by substrate ubiquitination, we find that increasing proteasome number and their recruitment to mitochondria support mitochondrial respiratory quiescence (MRQ). GSK3 triggers proteasome recruitment to the mitochondria by phosphorylating outer membrane proteins, such as VDAC, and suppressing mitochondrial fatty acid oxidation. This work defines a process that couples dynamic regulation of UPS activity to coordinated shifts in mitochondrial metabolism in fungi, Drosophila , and mammals during quiescence. Dynamic regulation of cellular proteostasis is linked to the metabolic state of quiescent cells in vivo. Here, the authors show, in multiple organisms, that shifts in the ubiquitin-proteome system are coupled to mitochondrial metabolic changes and subsequent respiratory quiescence.