Sirt5 preserves mitochondrial homeostasis to improve cardiac function in ischemia-reperfusion injury by inhibiting ANT2 lysine lactylation modification.

Myocardial ischemia-reperfusion (IR) injury, a prevalent heart disease, disrupts mitochondrial homeostasis, affecting heart energy metabolism. The role of mitochondrial protein Sirt5 in protecting the heart from IR injury is explored in mice. Reduced Sirt5 levels in IR-injured hearts correlate with increased protein lactylation and impaired mitochondrial function. Sirt5 overexpression mitigates, while its knockout worsens, mitochondrial and cardiac damage. Sirt5 interacts with ANT2, reducing its lysine lactylation to enhance its association with VDAC1. This interaction improves cardiac function post-injury. Targeting ANT2 lactylation may offer a therapeutic approach for cardiac injury.