SIRT3/AARS2 regulates SOD2 lactylation to determine neuronal fate in TBI.

Lactate accumulation is strongly associated with poor neurological outcomes in traumatic brain injury (TBI), creating a "lactate paradox" given its role as an energy substrate in the early stages of trauma. Imbalanced reactive oxygen species (ROS) act as cell injury factors throughout the pathological progression of TBI. This study aims to elucidate the key mechanisms connecting dysregulated lactate metabolism and cellular damage. We discovered that the high-lactate environment induced by TBI drives lysine lactylation of the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2), inhibiting its enzymatic activity and leading to mitochondrial ROS (mtROS) accumulation. Mechanistically, aminoacyl-tRNA synthetase 2 (AARS2) and NAD+-dependent deacetylase sirtuin 3 (SIRT3) coordinate SOD2 lactylation through "resident sensor-writer" and "dynamic patrol-eraser" modes, respectively. Proteomic analysis revealed that SOD2 lactylation triggers a reprogramming of its interaction network, shifting its interactome away from proteins involved in energy metabolism and toward those associated with proteostasis. In a mouse model of TBI, activating SIRT3 reversed SOD2 lactylation, restored its enzymatic function, and reduced neuronal apoptosis in the injured area. This study clarifies how AARS2/SIRT3-regulated SOD2 lactylation influences neuronal fate, providing potential targets for treating secondary injury in TBI.