Fundc1-KO Mouse

FUNDC1, or FUN14 domain containing 1, is an integral mitochondrial outer-membrane protein. It serves as a mitophagy receptor, playing a crucial role in regulating mitochondrial quality control and homeostasis. FUNDC1 is involved in multiple pathways, such as interacting with proteins related to mitochondrial dynamics (like DNM1L/DRP1 and OPA1) [6], and is associated with the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) [7]. Its dysregulation is implicated in various diseases, highlighting its biological importance. Genetic models, like KO mouse models, have been essential in studying its functions.

In liver fibrosis, FUNDC1 deletion protected against CCl4-induced hepatic anomalies and ferroptosis in mice. FUNDC1 interacted with GPx4 via its 96-133 amino acid domain, facilitating GPx4's mitochondrial translocation and degradation by mitophagy, triggering hepatocyte ferroptosis [1].

In doxorubicin-induced cardiotoxicity, FUNDC1 deficiency aggravated cardiac dysfunction, mitochondrial injury, and cardiomyocyte PANoptosis. FUNDC1 countered cytoplasmic release of mitochondrial DNA and activation of PANoptosome through interaction with TUFM [2].

In cardiac microvascular ischemia/reperfusion, genetic ablation of AMPKα1 or FUNDC1 abolished the beneficial effects of empagliflozin on the myocardial microvasculature and cardiac microvascular endothelial cells, as empagliflozin exerts its protective effects by activating FUNDC1-dependent mitophagy through the AMPKα1/ULK1 pathway [3].

In hypoxic pulmonary hypertension, Fundc1 KO mice were much resistant to hypoxic PH, while Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling. FUNDC1-mediated mitophagy activated the ROS-HIF1α pathway and promoted pulmonary artery smooth muscle cell proliferation [4].

In intestinal ischemia-reperfusion, elevated NET formation induced Fundc1 phosphorylation at Tyr18 in intestinal endothelial cells, inhibiting mitophagy, but AAV-Fundc1 transfection could reverse this process and ameliorate microvascular damage [5].

In osteoarthritis, FUNDC1 knockdown in vitro and knockout in vivo decreased mitophagy and exacerbated chondrocyte degeneration and OA progression [8].

In conclusion, FUNDC1 is crucial for mitochondrial quality control and homeostasis through its role in mitophagy. The use of KO/CKO mouse models has revealed its significance in various disease areas, including liver fibrosis, cardiotoxicity, cardiac microvascular ischemia/reperfusion, hypoxic pulmonary hypertension, intestinal ischemia/reperfusion, and osteoarthritis. Understanding FUNDC1's functions provides potential therapeutic targets for these diseases.