Immt, encoding inner membrane mitochondrial protein (also known as MIC60), is a key component of the mitochondrial contact site and cristae organizing system (MICOS). It is crucial for crista junction formation and maintaining inner mitochondrial membrane architecture. The function of Immt is associated with mitochondrial quality control, especially through mitophagy, which is important for multiple cellular metabolisms and regulated cell death [1,2]. Genetic models, such as KO/CKO mouse models, are valuable for studying Immt.

Genetic ablation of Immt in adult mice via tamoxifen-inducible ROSA-CreERT2 led to a lethal disruption of the MICOS complex. These mice showed increased mitochondria size, altered cristae morphology, defective intestinal muscle function (paralytic ileus) resulting in dehydration, and bone marrow hypocellularity [2]. In lung adenocarcinoma, high-IMMT expression was related to advanced disease stage, larger tumor size, intratumoral vascular invasion, and poorer patient prognosis. Knockdown of IMMT in A549 cells decreased proliferation [3]. In breast cancer, high IMMT expression was an independent diagnostic biomarker, associated with advanced clinical status and poor relapse-free survival. Experimental knockdown of IMMT impeded cell migration and viability, arrested the cell cycle, disturbed mitochondrial function, and increased ROS level and lipid peroxidation. Also, in breast cancer, suppressing IMMT inhibited cell proliferation through mitochondrial remodeling and metabolic regulation [4,7]. Burkholderia pseudomallei infection led to the K63-linked ubiquitination of IMMT by hijacking the host KLHL9-KLHL13-CUL3 E3 ligase complex, initiating mitophagy to evade killing [5,6].

In conclusion, Immt is essential for maintaining mitochondrial structure and function. The KO/CKO mouse models of Immt have revealed its significance in lethal disruptions of the MICOS complex and related physiological and pathological consequences. In cancer, Immt shows potential as a prognostic indicator and therapeutic target, highlighting its importance in understanding disease mechanisms and developing treatments [2,3,4,7].

References:

1. Zhang, Ting, Liu, Qian, Gao, Weihua, Sehgal, Sheikh Arslan, Wu, Hao. 2021. The multifaceted regulation of mitophagy by endogenous metabolites. In Autophagy, 18, 1216-1239. doi:10.1080/15548627.2021.1975914. https://pubmed.ncbi.nlm.nih.gov/34583624/

2. Rockfield, Stephanie M, Turnis, Meghan E, Rodriguez-Enriquez, Ricardo, Vogel, Peter, Opferman, Joseph T. 2024. Genetic ablation of Immt induces a lethal disruption of the MICOS complex. In Life science alliance, 7, . doi:10.26508/lsa.202302329. https://pubmed.ncbi.nlm.nih.gov/38467404/

3. Hiyoshi, Yasuhiro, Sato, Yuichi, Ichinoe, Masaaki, Masuda, Noriyuki, Naoki, Katsuhiko. 2019. Prognostic significance of IMMT expression in surgically-resected lung adenocarcinoma. In Thoracic cancer, 10, 2142-2151. doi:10.1111/1759-7714.13200. https://pubmed.ncbi.nlm.nih.gov/31583841/

4. Lin, Hung-Yu, Wu, Hsing-Ju, Chu, Pei-Yi. 2023. Multi-omics and experimental analysis unveil theragnostic value and immunological roles of inner membrane mitochondrial protein (IMMT) in breast cancer. In Journal of translational medicine, 21, 189. doi:10.1186/s12967-023-04035-4. https://pubmed.ncbi.nlm.nih.gov/36899366/

5. Nan, Dongqi, Rao, Chenglong, Tang, Zhiheng, Zou, Quanming, Li, Qian. 2024. Burkholderia pseudomallei BipD modulates host mitophagy to evade killing. In Nature communications, 15, 4740. doi:10.1038/s41467-024-48824-x. https://pubmed.ncbi.nlm.nih.gov/38834545/

6. Nan, Dongqi, Mao, Xuhu, Li, Qian. 2024. Burkholderia pseudomallei BipD initiates mitophagy to evade killing by hijacking host KLHL9-KLHL13-CUL3 E3 ligase to ubiquitinate IMMT. In Autophagy, 20, 2830-2832. doi:10.1080/15548627.2024.2403125. https://pubmed.ncbi.nlm.nih.gov/39265641/

7. Liu, Li, Zhao, Qingqing, Xiong, Daigang, Yang, Yan, Chen, Rui. 2024. Suppressing mitochondrial inner membrane protein (IMMT) inhibits the proliferation of breast cancer cells through mitochondrial remodeling and metabolic regulation. In Scientific reports, 14, 12766. doi:10.1038/s41598-024-63427-8. https://pubmed.ncbi.nlm.nih.gov/38834715/