Research Paper|Volume 14, Issue 2|pp 678—707

Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence

Yun Haeng Lee¹, Doyoung Choi², Geonhee Jang², Ji Yun Park¹, Eun Seon Song¹, Haneur Lee¹, Myeong Uk Kuk¹, Junghyun Joo¹, Soon Kil Ahn¹, Youngjoo Byun², Joon Tae Park¹

¹Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
²College of Pharmacy, Korea University, Sejong 30019, Republic of Korea

* Equal contribution

Received: August 12, 2021Accepted: January 14, 2022Published: January 30, 2022

https://doi.org/10.18632/aging.203858

Copyright: © 2022 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Senescence is a distinct set of changes in the senescence-associated secretory phenotype (SASP) and leads to aging and age-related diseases. Here, we screened compounds that could ameliorate senescence and identified an oxazoloquinoline analog (KB1541) designed to inhibit IL-33 signaling pathway. To elucidate the mechanism of action of KB1541, the proteins binding to KB1541 were investigated, and an interaction between KB1541 and 14–3–3ζ protein was found. Specifically, KB1541 interacted with 14–3–3ζ protein and phosphorylated of 14–3–3ζ protein at serine 58 residue. This phosphorylation increased ATP synthase 5 alpha/beta dimerization, which in turn promoted ATP production through increased oxidative phosphorylation (OXPHOS) efficiency. Then, the increased OXPHOS efficiency induced the recovery of mitochondrial function, coupled with senescence alleviation. Taken together, our results demonstrate a mechanism by which senescence is regulated by ATP synthase 5 alpha/beta dimerization upon fine-tuning of KB1541-mediated 14–3–3ζ protein activity.