DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53

Abstract

DNA polymerase gamma (PolG) is the major polymerase of mitochondrial DNA (mtDNA) and essential for stabilizing mitochondrial function. Vascular calcification (VC) is common senescence related degenerative pathology phenomenon in the end-stage of multiple chronic diseases. Mitochondrial dysfunction was often observed in calcified vessels, but the function and mechanism of PolG in the calcification process was still unknown. The present study found PolG D257A/D257A mice presented more severe calcification of aortas than wild type (WT) mice with vitamin D3 (Vit D3) treatment, and this phenomenon was also confirmed in vitro. Mechanistically, PolG could enhance the recruitment and interaction of p53 in calcification condition to recover mitochondrial function and eventually to resist calcification. Meanwhile, we found the mutant PolG (D257A) failed to achieve the same rescue effects, suggesting the 3'-5' exonuclease activity guarantee the enhanced interaction of p53 and PolG in response to calcification stimulation. Thus, we believed that it was PolG, not mutant PolG, could maintain mitochondrial function and attenuate calcification in vitro and in vivo. And PolG could be a novel potential therapeutic target against calcification, providing a novel insight to clinical treatment.

Oxidized phospholipid POVPC contributes to vascular calcification by triggering ferroptosis of vascular smooth muscle cells

“…Moreover, it has been shown that correcting mitochondrial dysfunction suppresses cardiovascular calcification. 52,53 Previous studies have shown that POVPC increases the production of ROS and impairs mitochondrial function. 18,19 Consistently, we found that POVPC stimulates oxidative stress and mitochondrial dysfunction, as shown by increased cytosolic ROS levels, impairment of MMP, and decreased ATP contents.…”

“…Local ROS generation does not only lead to mitochondrial damage but also affects the redox status. Moreover, it has been shown that correcting mitochondrial dysfunction suppresses cardiovascular calcification 52,53 . Previous studies have shown that POVPC increases the production of ROS and impairs mitochondrial function 18,19 .…”