TIMM44, short for translocase of inner mitochondrial membrane 44, is crucial for maintaining mitochondrial functions. It anchors mitochondrial heat-shock protein 70 (mtHsp70) to the TIM23 complex in the inner mitochondrial membrane, facilitating the import of mitochondria-targeted preproteins into the mitochondrial matrix, which is dependent on the inner membrane potential and ATP hydrolysis on the ATPase domain of mtHsp70 [5]. Mitochondrial integrity and function are essential for various cellular processes, thus TIMM44 is important for overall cell function and is involved in pathways like angiogenesis, cell proliferation, and apoptosis [1,2,3,4].

In glioma, depletion of TIMM44 using lentiviral shRNA or Nuclease technology KO method robustly inhibited cell viability, proliferation, and migration. It also led to mitochondrial complex I inhibition, ATP depletion, and apoptosis [1]. In endothelial cells, silencing or knocking out TIMM44 disrupted mitochondrial functions, inhibited cell proliferation, migration, and in-vitro capillary tube formation, and also inhibited retinal angiogenesis in vivo [2]. In bladder cancer cells, the TIMM44 blocker MB-10 induced apoptosis and cell cycle arrest, and genetic depletion of TIMM44 through CRISPR-Cas9 also showed anti-bladder cancer cell activity [3].

In conclusion, TIMM44 is essential for mitochondrial function and plays a significant role in processes related to cancer and angiogenesis. The use of KO models in glioma, endothelial cells, and bladder cancer has revealed its importance in cell viability, proliferation, and migration, making it a potential therapeutic target for diseases such as glioma, bladder cancer, and those with abnormal angiogenesis [1,2,3].

References:

1. Guo, Yi-Zhuo, Chen, Gang, Huang, Man, Cao, Cong, Liu, Fang. 2022. TIMM44 is a potential therapeutic target of human glioma. In Theranostics, 12, 7586-7602. doi:10.7150/thno.78616. https://pubmed.ncbi.nlm.nih.gov/36438483/

2. Ma, Zhou-Rui, Li, Hong-Peng, Cai, Shi-Zhong, Zhen, Yun-Fang, Wang, Qian. 2023. The mitochondrial protein TIMM44 is required for angiogenesis in vitro and in vivo. In Cell death & disease, 14, 307. doi:10.1038/s41419-023-05826-9. https://pubmed.ncbi.nlm.nih.gov/37147302/

3. Zhang, Lifeng, Shi, Xiaokai, Zhang, Lei, Zuo, Li, Gao, Shenglin. 2024. A first-in-class TIMM44 blocker inhibits bladder cancer cell growth. In Cell death & disease, 15, 204. doi:10.1038/s41419-024-06585-x. https://pubmed.ncbi.nlm.nih.gov/38467612/

4. Yu, Xiaohui, Li, Yujiao, Ding, Yumei, Ding, Ning, Lu, Ming. 2020. HuR Promotes Ovarian Cancer Cell Proliferation by Regulating TIMM44 mRNA Stability. In Cell biochemistry and biophysics, 78, 447-453. doi:10.1007/s12013-020-00939-w. https://pubmed.ncbi.nlm.nih.gov/32901414/

5. Wang, Yu, Katayama, Akihiro, Terami, Takahiro, Makino, Hirofumi, Wada, Jun. 2015. Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes. In Metabolism: clinical and experimental, 64, 677-88. doi:10.1016/j.metabol.2015.02.004. https://pubmed.ncbi.nlm.nih.gov/25749183/