Mfn2, a GTPase dynamin-like protein of the outer mitochondrial membrane encoded by the MFN2 gene on chromosome 1p, is mainly involved in mitochondrial functions such as fusion, axonal transport, interorganellar communication and mitophagy. It is also associated with pathways like those regulating T-cell metabolic fitness, EGFR signaling, and autophagy, and is crucial for maintaining cellular homeostasis [5]. Genetic models, especially knockout (KO) mouse models, have been pivotal in understanding its functions.

In CD8+ T cells, genetic ablation of Mfn2 dampens mitochondrial metabolism and function, promoting tumor progression. Mfn2 enhances mitochondria-ER contact by interacting with SERCA2, facilitating mitochondrial Ca2+ influx and preventing excessive Ca2+ accumulation [1]. In clear cell renal cell carcinoma (ccRCC), Mfn2 is down-regulated. Kidney-specific knockout of Mfn2 leads to EGFR pathway activation and malignant lesions in the kidney [2]. In ovarian cancer, genetic activation of Mfn2 promotes mitochondrial fusion, reduces ROS, and suppresses cancer progression [3]. In the context of acute kidney injury, Lrrk2-deficient mice with MFN2 accumulation exhibit less severe AKI, while overexpression of LRRK2 promotes MFN2 degradation and exaggerates mitochondrial damage [4].

In conclusion, Mfn2 is essential for multiple biological processes, especially those related to mitochondrial function. KO/CKO mouse models have revealed its role in various disease conditions, including cancer and kidney injury. Understanding Mfn2's functions provides potential therapeutic targets for these diseases.