Marchf5, also known as MITOL, MARCH5, or RNF153, is an outer mitochondrial membrane-localized E3 ubiquitin ligase. It plays a crucial role in mitochondrial quality control, regulating mitochondrial dynamics, formation of mitochondria-ER contacts, and mitophagy. It is also involved in apoptosis regulation and has a connection with various cellular metabolic and stress-response pathways. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions [1,2,3,4].

In KO/CKO mouse models, MITOL deletion in the bone marrow led to hematopoietic stem cell (HSC) exhaustion and impairment of bone marrow reconstitution due to prolonged ER stress-induced apoptosis regulated by IRE1α, indicating its role in hematopoietic homeostasis [4]. In cancer research, deleting MARCHF5 in cell lines dependent on BAK conferred resistance to BH3-mimetic drugs, revealing a new apoptosis-regulating mechanism [2]. MARCH5 was also found to regulate hypoxia-induced mitophagy by ubiquitylating and degrading FUNDC1, showing its function in fine-tuning mitochondrial quality [3].

In conclusion, Marchf5 is essential for mitochondrial quality control, apoptosis regulation, and hematopoietic homeostasis. Studies using KO/CKO mouse models have provided insights into its role in hematopoietic-related diseases and cancer. These findings contribute to a better understanding of the underlying mechanisms of these diseases and may offer potential therapeutic targets [2,3,4].

References:

1. Nagashima, Shun, Ito, Naoki, Shiiba, Isshin, Shimura, Hiroki, Yanagi, Shigeru. . Ubiquitin-mediated mitochondrial regulation by MITOL/MARCHF5 at a glance. In Journal of biochemistry, 173, 1-11. doi:10.1093/jb/mvac092. https://pubmed.ncbi.nlm.nih.gov/36346121/

2. Huang, Allan Shuai, Chin, Hui San, Reljic, Boris, van Delft, Mark F, Dewson, Grant. 2022. Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins. In Cell death and differentiation, 30, 632-646. doi:10.1038/s41418-022-01067-z. https://pubmed.ncbi.nlm.nih.gov/36171332/

3. Chen, Ziheng, Liu, Lei, Cheng, Qi, Zhu, Yushan, Chen, Quan. 2017. Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy. In EMBO reports, 18, 495-509. doi:10.15252/embr.201643309. https://pubmed.ncbi.nlm.nih.gov/28104734/

4. Ma, Wenjuan, Ahmad, Shah Adil Ishtiyaq, Hashimoto, Michihiro, Umemoto, Terumasa, Suda, Toshio. 2024. MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response. In The EMBO journal, 43, 339-361. doi:10.1038/s44318-024-00029-0. https://pubmed.ncbi.nlm.nih.gov/38238476/