IDH3A Inhibits Cardiomyocyte Hypertrophy via Elevating α-Ketoglutarate Level
10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.2025.0211
- VernacularTitle:α-酮戊二酸介导异柠檬酸脱氢酶3A发挥抑制心肌细胞肥大的作用
- Author:
Huayan WU
1
;
Yihong WEN
1
;
Hengli ZHAO
2
;
Yuan GAO
2
;
Chuanmeng ZHOU
2
;
Ya WANG
1
;
Jiening ZHU
2
;
Zhixin SHAN
1
Author Information
1. School of Medicine， South China University of Technology， Guangzhou 510006， China
2. Guangdong Provincial People’s Hospital， Guangdong Academy of Medical Sciences， Southern Medical University， Guangzhou 510080， China
- Publication Type:Journal Article
- Keywords:
cardiac hypertrophy;
isocitrate dehydrogenase 3A;
α-ketoglutarate;
cardiomyocytes;
mitochondria
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2025;46(2):275-283
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate the regulatory effect and potential mechanisms of isocitrate dehydrogenase 3A （IDH3A） on cardiomyocyte hypertrophy. MethodsThe expression of IDH3A in the myocardium of healthy volunteers （n=10） and patients with heart failure （HF） （n=10）， and in the myocardium of mice subjected to transverse aortic constriction （TAC） surgery and sham operation， as well as in phenylephrine （PE）-induced neonatal rat ventricular cardiomyocytes （NRVCs）， was assessed by real-time quantitative polymerase chain reaction （RT-qPCR） and Western blot assay. The effect of adenovirus-mediated overexpression of IDH3A on the expression of hypertrophy-related genes in PE-induced NRVCs was also evaluated. The effect of IDH3A on NRVCs area was examined by phalloidin staining assay. A mutant of IDH3A with abolished enzymatic activity， IDH3A_D208A， was generated through site-directed mutagenesis. The impact of this IDH3A mutant on the hypertrophic phenotype， ATP and ROS levels in NRVCs was evaluated to investigate whether the regulatory role of IDH3A in cardiomyocyte hypertrophy was dependent on its enzymatic activity. The effect of exogenous α-ketoglutaric acid （AKG） on cardiomyocyte hypertrophy was also detected by Western blot and phalloidin staining assay， respectively. ResultsIDH3A was significantly decreased in the myocardium of HF patients， in the myocardium of TAC-operated mice， and in PE-induced NRVCs （P = 0.005 2，P = 0.026 6，P = 0.041 3 and P = 0.006 6， respectively）. Overexpression of IDH3A markedly suppressed the expression of hypertrophy-related genes and the increase of cell size of PE-induced NRVCs （P < 0.000 1， P = 0.000 1 and P = 0.000 2， respectively）. The ATP and ROS analysis indicated that IDH3A inhibited the increases of ATP and ROS levels in PE-induced NRVCs （P = 0.001 2 and P<0.000 1， respectively）， whereas the enzymatically inactive IDH3A mutant lacked this effect. Exogenous AKG provision could， but overexpression of IDH3A mutant failed to suppress PE-induced NRVCs hypertrophy. ConclusionIDH3A inhibits cardiomyocyte hypertrophy via elevating AKG level， providing scientific evidence for study on IDH3A-based treatment of cardiac hypertrophy.
