Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm

Wang, H.; Kazaleh, M.; Gioscia-Ryan, R. A.; Millar, J.; Temprano-Sagrera, G.; Wood, S.; Van Den Burgh, F.; Blin, M. G.; Wragg, K. M.; Luna, A.; Hawkins, R. B.; Soleimanpour, S. A.; Sabater-Lleal, M.; Shu, C.; Beard, D. A.; Ailawadi, G.; Deng, J. C.; Goldstein, D. R.; Salmon, M.

doi:10.1101/2024.10.30.621201

bioRxiv · 10.1101/2024.10.30.621201

Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm

Wang, H.·Kazaleh, M.·Gioscia-Ryan, R. A.·Millar, J.·Temprano-Sagrera, G.·Wood, S.·Van Den Burgh, F.·Blin, M. G.·Wragg, K. M.·Luna, A.·Hawkins, R. B.·Soleimanpour, S. A.·Sabater-Lleal, M.·Shu, C.·Beard, D. A.·Ailawadi, G.·Deng, J. C.·Goldstein, D. R.·Salmon, M.

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Abstract

Abdominal aortic aneurysms (AAAs) are a degenerative aortic disease and associated with hallmarks of aging, such as mitophagy. Despite this, the exact associations among mitophagy, aging, and AAA progression remain unknown. In our study, gene expression analysis of human AAA tissue revealed downregulation of mitophagy pathways, mitochondrial structure, and function-related proteins. Human proteomic analyses identified decreased levels of mitophagy mediators PINK1 and Parkin. Aged mice and, separately, a murine AAA model showed reduced mitophagy in aortic vascular smooth muscle cells (VSMCs) and PINK1 and Parkin expression. Parkin knockdown in VSMCs aggravated AAA dilation in murine models, with elevated mitochondrial ROS and impaired mitochondrial function. Importantly, inhibiting USP30, an antagonist of the PINK1/Parkin pathway, increased mitophagy in VSMCs, improved mitochondrial function, and reduced AAA incidence and growth. Our study elucidates a critical mechanism that proposes AAAs as an age-associated disease with altered mitophagy, introducing new potential therapeutic approaches.

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Wang, H., Kazaleh, M., Gioscia-Ryan, R. A., Millar, J., Temprano-Sagrera, G., Wood, S., Van Den Burgh, F., Blin, M. G., Wragg, K. M., Luna, A., Hawkins, R. B., Soleimanpour, S. A., Sabater-Lleal, M., Shu, C., Beard, D. A., Ailawadi, G., Deng, J. C., Goldstein, D. R., Salmon, M.. 2024-11-01. Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm. https://doi.org/10.1101/2024.10.30.621201

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