Spermidine Enhances Mitochondrial Function and Mitigates Aortic Valve Calcification: Implications for DNA Methyltransferase-1 Activity

Naaleum Song; Eunhye Ji; Jeong Eun Yu; Kyoung-Hee Choi; Dae-Hee Kim; Jong-Min Song; Duk-Hyun Kang; Jae-Kwan Song; Jiyoung Yu; Kyunggon Kim; Sahmin Lee; Elena Aikawa

doi:10.1016/j.jacbts.2024.11.011

Spermidine Enhances Mitochondrial Function and Mitigates Aortic Valve Calcification: Implications for DNA Methyltransferase-1 Activity

JACC Basic Transl Sci. 2025 Mar;10(3):345-366. doi: 10.1016/j.jacbts.2024.11.011. Epub 2025 Feb 12.

Authors

Affiliations

¹ Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
² Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
³ Convergence Medicine Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
⁴ Convergence Medicine Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea; Department of Digital Medicine, Brain Korea 21 plus, University of Ulsan College of Medicine and Department of Convergence Medicine and Asan Institute of Life Science, Asan Medical Center, Seoul, Republic of Korea.
⁵ Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: sahmin.lee@amc.seoul.kr.
⁶ Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: eaikawa@bwh.harvard.edu.

Abstract

Aortic stenosis (AS) is a severe heart valve disease marked by calcification, leading to heart failure. This study examined mitochondrial function in human aortic valve interstitial cells isolated from patients with AS and tested spermidine, an autophagy inducer as AS treatment. Spermidine treatment reduced fibrosis and calcification in human aortic valve interstitial cells and improved these features in spermidine-treated mice. The AKT-TP53-DNMT1-PPARG pathway was implicated, and DNA methyltransferase 1 inhibition by 5-azacytidine enhanced mitochondrial biogenesis by reducing mitochondrial DNA hypermethylation. These findings suggest that spermidine or DNA methyltransferase 1 inhibition could prevent aortic valve disease by improving mitochondrial function.

Keywords: DNA methyltransferase 1; aging; aortic stenosis; mitochondrial function; spermidine.