Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Cell Death Dis. 2023 Jul 5;14(7):398. doi: 10.1038/s41419-023-05910-0.
TIMM13 (translocase of inner mitochondrial membrane 13) located at the mitochondrial intermembrane space is vital for the integrity and function of mitochondria. We found that the mitochondrial protein TIMM13 is upregulated in human OS tissues and cells. In patient-derived primary OS cells and established cell lines, TIMM13 shRNA or knockout provoked mitochondrial dysfunction, causing mitochondrial depolarization, reactive oxygen species production, and oxidative injury, as well as lipid peroxidation, DNA damage, and ATP depletion. Moreover, TIMM13 depletion provoked OS cell apoptosis and inhibited cell proliferation and migration. Conversely, ectopic TIMM13 overexpression increased ATP contents, enhancing OS cell proliferation and migration. Moreover, we discovered that Akt-mTOR activation was inhibited with TIMM13 depletion in primary OS cells. Further studies revealed that HOXC13 (Homeobox C13)-dependent TIMM13 transcription was significantly increased in OS tissues and cells. Whereas TIMM13 transcription and expression were decreased following HOXC13 silencing in primary OS cells. In vivo, TIMM13 KO potently inhibited OS xenograft growth in the proximal tibia of nude mice. TIMM13 KO also induced Akt-mTOR inactivation, ATP depletion, oxidative injury, and apoptosis in the in situ OS tumors. Together, upregulation of the mitochondrial protein TIMM13 is important for OS cell growth, representing a novel and promising therapeutic target.
TIMM13（线粒体内膜转位酶 13）位于线粒体膜间隙，对线粒体的完整性和功能至关重要。我们发现 TIMM13 在人骨肉瘤组织和细胞中上调。在患者来源的原代骨肉瘤细胞和建立的细胞系中，TIMM13 shRNA 或敲除会引起线粒体功能障碍，导致线粒体去极化、活性氧产生和氧化损伤，以及脂质过氧化、DNA 损伤和 ATP 耗竭。此外，TIMM13 耗竭会引发骨肉瘤细胞凋亡并抑制细胞增殖和迁移。相反，异位 TIMM13 过表达会增加 ATP 含量，增强骨肉瘤细胞的增殖和迁移。此外，我们发现 TIMM13 耗竭会抑制原代骨肉瘤细胞中的 Akt-mTOR 激活。进一步的研究表明，HOXC13（同源盒 C13）依赖性 TIMM13 转录在骨肉瘤组织和细胞中显著增加。而在原代骨肉瘤细胞中沉默 HOXC13 后，TIMM13 的转录和表达降低。在体内，TIMM13 KO 可有效抑制裸鼠胫骨近端骨肉瘤异种移植物的生长。TIMM13 KO 还可诱导原位骨肉瘤肿瘤中 Akt-mTOR 失活、ATP 耗竭、氧化损伤和凋亡。总之，上调线粒体蛋白 TIMM13 对骨肉瘤细胞的生长很重要，代表了一个新的有前途的治疗靶点。
