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Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner
Choi, Soo Young Rath, Meghan E. Saredy, Jason Jovin, Daniel G. Sayoc, Jacqueline Park, Hye-Sang Eguchi, Satoru Rizzo, Victor
Choi, Soo Young
Rath, Meghan E.
Saredy, Jason
Jovin, Daniel G.
Sayoc, Jacqueline
Park, Hye-Sang
Eguchi, Satoru
Rizzo, Victor
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Journal article
Date
2022-01-29
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Kinesiology
Cardiovascular Sciences
Medicine
Cardiovascular Sciences
Medicine
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http://dx.doi.org/10.1016/j.redox.2022.102252
Abstract
Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wildtype mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.
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Citation
Junchul Shin, Soon-Gook Hong, Soo Young Choi, Meghan E. Rath, Jason Saredy, Daniel G. Jovin, Jacqueline Sayoc, Hye-Sang Park, Satoru Eguchi, Victor Rizzo, Rosario Scalia, Hong Wang, Steven R. Houser, Joon-Young Park, Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner, Redox Biology, Volume 50, 2022, 102252, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2022.102252.
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Elsevier
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Redox Biology, Vol. 50
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