Ftmt, short for ferritin mitochondrial, is a type of ferritin that stores excess intracellular iron within the mitochondria. It shares sequence homology with cytosolic ferritin but has distinct functions and regulations. Ftmt is crucial for maintaining iron homeostasis, a process essential for cells as iron is indispensable yet toxic in excess. It may be involved in multiple pathways related to iron-mediated cell processes, such as those related to oxidative stress response and cell death regulation [1].

In various disease-related studies, Ftmt shows significant impacts. In high-glucose-treated cardiac fibroblasts, Ftmt-dependent mitophagy confers ferroptosis resistance. High glucose upregulates FOXA1, which promotes Ftmt transcription, enhancing mitophagy [2]. In cerebral ischemia-reperfusion injury, Ftmt deficiency exacerbates neuronal apoptosis via the mitochondria-dependent and ER stress pathways, while its overexpression protects neurons by improving mitochondrial function, reducing iron overload, and enhancing glucose metabolism [3]. In a kainic acid-induced mouse epilepsy model, knockdown of the Ftmt gene increases intracellular free iron, promotes neuronal ferroptosis, and exacerbates epileptic brain activity [4]. In ischaemic stroke models, Ftmt knockout mice experience more severe brain damage and ferroptosis-related molecular changes, while Ftmt overexpression reverses these effects [5].

In summary, Ftmt is essential for maintaining iron homeostasis and plays a protective role in multiple disease conditions, including those related to oxidative stress-induced cell damage such as in cerebral ischemia-reperfusion, epilepsy, and ischaemic stroke. Gene knockout models of Ftmt have been instrumental in revealing its role in these disease-associated biological processes, highlighting its potential as a therapeutic target.

References:

1. Yanatori, Izumi, Nishina, Sohji, Kishi, Fumio, Hino, Keisuke. . Newly uncovered biochemical and functional aspects of ferritin. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e23095. doi:10.1096/fj.202300918R. https://pubmed.ncbi.nlm.nih.gov/37440196/

2. Xu, Cheng-Zhang, Gao, Qing-Yuan, Gao, Guang-Hao, Wang, Jing-Feng, Zhang, Hai-Feng. 2024. FTMT-dependent mitophagy is crucial for ferroptosis resistance in cardiac fibroblast. In Biochimica et biophysica acta. Molecular cell research, 1871, 119825. doi:10.1016/j.bbamcr.2024.119825. https://pubmed.ncbi.nlm.nih.gov/39168410/

3. Wang, Peina, Cui, Yanmei, Liu, Yuanyuan, Zhao, Yashuo, Chang, Yan-Zhong. 2022. Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion. In Redox biology, 57, 102475. doi:10.1016/j.redox.2022.102475. https://pubmed.ncbi.nlm.nih.gov/36179435/

4. Song, Yu, Gao, Mengjiao, Wei, Boyang, Zou, Junjie, Guo, Yanwu. . Mitochondrial ferritin alleviates ferroptosis in a kainic acid-induced mouse epilepsy model by regulating iron homeostasis: Involvement of nuclear factor erythroid 2-related factor 2. In CNS neuroscience & therapeutics, 30, e14663. doi:10.1111/cns.14663. https://pubmed.ncbi.nlm.nih.gov/38439636/

5. Wang, Peina, Cui, Yanmei, Ren, Qianqian, Chang, Shiyang, Chang, Yan-Zhong. 2021. Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis. In Cell death & disease, 12, 447. doi:10.1038/s41419-021-03725-5. https://pubmed.ncbi.nlm.nih.gov/33953171/