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

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.

SUBMITTER: Lee YH

PROVIDER: S-EPMC8833107 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Lee Yun Haeng YH Choi Doyoung D Jang Geonhee G Park Ji Yun JY Song Eun Seon ES Lee Haneur H Kuk Myeong Uk MU Joo Junghyun J Ahn Soon Kil SK Byun Youngjoo Y Park Joon Tae JT

Aging 20220130 2

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 ...[more]

PMID: 35093936

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Project description:Misfolded ?-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded ?-synuclein is limited. Using brains of mice lacking ?-, ?-, and ?-synuclein, we report that extracellular monomeric ?-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit ?, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded ?-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that ?-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity. SIGNIFICANCE STATEMENT:Misfolded ?-synuclein aggregations in the form of Lewy bodies have been shown to be a pathological hallmark in histological staining of Parkinson's disease (PD) patient brains. It is known that misfolded ?-synuclein is a key driver in PD pathogenesis, but the physiological role of unfolded monomeric ?-synuclein remains unclear. Using neuronal cocultures and isolated brain mitochondria of ?-, ?-, and ?-synuclein knock-out mice and monomeric ?-synuclein, this current study shows that ?-synuclein in its unfolded monomeric form improves ATP synthase efficiency and mitochondrial function. The ability of monomeric ?-synuclein to enhance ATP synthase efficiency under physiological conditions may be of importance when ?-synuclein undergoes the misfolding and aggregation reported in PD.

Dataset Information

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

Publications

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

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