RND3 Enhances Cardiac Glucose Metabolism Through Inhibiting ACAT1-Dependent PDHA1 Acetylation and Protects Against...

Area of Science:

• Cardiovascular Biology
• Mitochondrial Metabolism
• Molecular Cardiology

Background:

• Metabolic disturbances contribute to myocardial ischemia-reperfusion (I/R) injury, but mechanisms are unclear.
• RND3, a small GTPase, is linked to cardiovascular disorders, but its mitochondrial role in cardiac metabolism and I/R injury is unknown.

Purpose of the Study:

• To investigate the mitochondrial localization and function of RND3 in cardiac energy metabolism.
• To determine the role of RND3 in myocardial ischemia-reperfusion (I/R) injury.

Main Methods:

• Established a murine model of myocardial I/R injury.
• Generated cardiomyocyte-specific knockout and overexpression of RND3 mice.
• Utilized advanced metabolic assays (e.g., 13C-NMR, PET/CT, Seahorse) and molecular techniques (RNA-seq, Co-IP, Mass Spectrometry).

Main Results:

• RND3 deletion impaired glucose oxidation, increased fatty acid oxidation, and worsened cardiac dysfunction and mortality.
• RND3 directly binds ACAT1, disrupting its interaction with PDHA1, promoting PDHA1 acetylation, and enhancing glucose oxidation.
• RND3 expression decreased post-I/R; loss of RND3 sensitized hearts to I/R injury, while RND3 overexpression conferred protection.

Conclusions:

• RND3 is a novel mitochondrial regulator of glucose oxidation that protects the heart against I/R injury.
• Therapeutic restoration of RND3 shows promise for mitigating myocardial damage and restoring metabolic homeostasis in I/R injury.