TUFM, also known as mitochondrial Tu translation elongation factor, is a nuclear-encoded mitochondrial protein well-known for its role in mitochondrial protein translation. It is evolutionarily conserved from prokaryotes to eukaryotes. Dysregulation of TUFM has been associated with mitochondrial disorders. TUFM is also involved in regulating programmed cell death processes like autophagy, apoptosis, necroptosis, and pyroptosis, and has diverse roles in viral infection, cancer, and other diseases [4].

In a mouse model of doxorubicin-induced cardiotoxicity, FUNDC1 deficiency aggravated the damage, while FUNDC1 interacted with TUFM to counter cytoplasmic release of mitochondrial DNA and activation of PANoptosome, protecting against cardiomyocyte PANoptosis [1]. In traumatic brain injury mouse models, lactylation of Tufm at K286 inhibited its interaction with Tomm40, suppressing Tufm-mediated mitophagy and increasing neuronal apoptosis. The knockin of a lactylation-deficient TufmK286R mutant rescued the situation [2]. In NASH mouse models, increased MRG15 in NASH livers interacted with and deacetylated TUFM, leading to its accelerated degradation by the mitochondrial ClpXP protease system, impaired mitophagy, and NASH progression. Blocking MRG15 expression protected the liver by increasing TUFM stability [3].

In summary, TUFM plays essential roles in mitochondrial protein translation and the regulation of programmed cell death processes. Studies using gene-knockout or conditional-knockout mouse models in diseases such as doxorubicin-induced cardiotoxicity, traumatic brain injury, and NASH have revealed its significance in these disease conditions. These findings may provide potential therapeutic targets for related diseases.

References:

1. Bi, Yaguang, Xu, Haixia, Wang, Xiang, Ren, Jun, Zhang, Yingmei. 2022. FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM. In Cell death & disease, 13, 1020. doi:10.1038/s41419-022-05460-x. https://pubmed.ncbi.nlm.nih.gov/36470869/

2. Weng, Weiji, He, Zhenghui, Ma, Zixuan, Jiang, Jiyao, Feng, Junfeng. 2024. Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury. In Cell death and differentiation, 32, 530-545. doi:10.1038/s41418-024-01408-0. https://pubmed.ncbi.nlm.nih.gov/39496783/

3. Tian, Cheng, Min, Xuewen, Zhao, Yongxu, Zhou, Ben, Ding, Qiurong. 2022. MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM. In Journal of hepatology, 77, 1491-1503. doi:10.1016/j.jhep.2022.07.017. https://pubmed.ncbi.nlm.nih.gov/35985547/

4. Liu, Ning, Pang, Bo, Kang, Longfei, Jiang, Xia, Zhou, Chuan-Min. 2024. TUFM in health and disease: exploring its multifaceted roles. In Frontiers in immunology, 15, 1424385. doi:10.3389/fimmu.2024.1424385. https://pubmed.ncbi.nlm.nih.gov/38868764/