Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient Tufm^K286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

创伤性脑损伤 （TBI） 后的乳酸积累是有害的。然而，乳酰化是否被触发并参与 TBI 的恶化仍然未知。在这里，我们首先报道了 Tufm 乳酸化途径诱导 TBI 中的神经元凋亡。在 TBI 患者和具有受控皮质影响 （CCI） 的小鼠的脑组织中以及神经元损伤细胞模型中发现乳酰化显着增加。Tufm 是线粒体自噬的一个关键因素，经过筛选并确定大部分是乳酸化的。检测到 Tufm 在 K286 位点被乳酰化，乳酰化抑制 Tufm 和 Tomm40 在线粒体上的相互作用。然后抑制 Tufm 的线粒体分布。因此，Tufm 介导的线粒体自噬受到抑制，而线粒体诱导的神经元凋亡增加。相比之下，小鼠乳酰化缺陷型 Tufm^K286R 突变体的敲入可挽救 Tufm 和 Tufm 介导的线粒体自噬的线粒体分布，并改善 CCI 后的功能结局。同样，轻度低温作为神经保护的关键治疗方法，有助于下调 Tufm 乳酸化，增加 Tufm 介导的线粒体自噬，减轻神经元凋亡，并最终改善 TBI 的结果。因此揭示了神经元凋亡中的一种新的分子机制，即 TBI 启动的抑制线粒体自噬的 Tufm 乳酸化。