LETM1 deacetylation attenuates calcium overload-mediated mitochondrial injury and protects the intestine from ischemia/reperfusion damage

Mitochondrial dysfunction is a central contributor to the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. This dysfunction is closely linked to mitochondrial calcium overload and excessive Reactive Oxygen Species (ROS) production, culminating in cellular Apoptosis. Leucine Zipper And EF-Hand Containing Transmembrane Protein 1 (LETM1), a key regulator of mitochondrial permeability, is essential for cellular homeostasis and survival. However, the role and underlying mechanism of LETM1 in intestinal I/R injury remain poorly understood. Here, we observed that LETM1 expression was significantly downregulated in intestinal tissues following I/R. AAV9-mediated overexpression of LETM1 significantly alleviated mitochondrial dysfunction. We further found that the acetylation status at lysine 597 (K597) modulates the stability of LETM1 in Caco-2 cells. LETM1 was identified as a downstream target of mitochondrial deacetylase Sirtuin 3 (SIRT3), and its knockdown significantly impaired the protective effects of SIRT3 in vitro. Collectively, our findings provide the first evidence that LETM1 serves as a protective target against calcium overload-induced mitochondrial dysfunction and Apoptosis during intestinal I/R injury. These findings highlight the therapeutic potential of targeting LETM1 deacetylation as a novel strategy for intestinal I/R injury prevention.

Apoptosis; Intestinal I/R; LETM1; Mitochondria dysfunction; SIRT3.