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bioRxiv · 10.1101/787812

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

Ma, D.·Zheng, B.·Liu, H.-l.·Zhao, Y.-b.·Liu, X.·Zhang, X.·Li, Q.·Shi, W.-b.·Suzuki, T.·Wen, J.-k.
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Abstract

Though dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Klf5, an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here we show that Klf5 downregulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of Ang II-induced AAA by facilitating ROS formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eIF5a transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with Mfn1. Accordingly, decreased expression of eIF5a elicited by Klf5 downregulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

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Ma, D., Zheng, B., Liu, H.-l., Zhao, Y.-b., Liu, X., Zhang, X., Li, Q., Shi, W.-b., Suzuki, T., Wen, J.-k.. 2019-09-30. eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs. https://doi.org/10.1101/787812

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