{"title":"Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.","authors":"Weiji Weng, Zhenghui He, Zixuan Ma, Jialin Huang, Yuhan Han, Qiyuan Feng, Wenlan Qi, Yidong Peng, Jiangchang Wang, Jiacheng Gu, Wenye Wang, Yong Lin, Gan Jiang, Jiyao Jiang, Junfeng Feng","doi":"10.1038/s41418-024-01408-0","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>K286R</sup> 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.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":null,"pages":null},"PeriodicalIF":13.7000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death and Differentiation","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41418-024-01408-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 TufmK286R 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.
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