Hint2-flox Mouse

Hint2, or Histidine triad nucleotide-binding protein 2, is a dimeric protein belonging to the histidine triad protein superfamily. Predominantly expressed in the liver, pancreas, and adrenal gland, it localizes to the mitochondrion. Hint2 binds nucleotides and catalyzes the hydrolysis of nucleotidyl substrates. It is a key regulator of multiple biological processes, including mitochondria-dependent apoptosis, mitochondrial protein acetylation, and steroidogenesis [6].

In cardiovascular diseases, Hint2 has shown protective effects. In mouse models, Hint2 overexpression inhibited the MCU complex-mitochondrial calcium overload-mitochondrial fission and apoptosis pathway, attenuating cardiac microvascular ischemia-reperfusion injury [1]. Hint2 overexpressing mice also exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress, while Hint2 deficiency in mice worsened the hypertrophic phenotype, suggesting Hint2 alleviates pressure overload-induced cardiac remodelling by influencing mitochondrial complex I [2]. In a myocardial infarction mouse model, Hint2 deficiency led to deteriorative oxidative stress and exacerbated myocardial dysfunction [3].

In diabetes-related research, Hint2 reduced ROS-induced oxidative stress and ferroptosis by regulating MCU in a mouse model of diabetic nephropathy [7].

In cancer, in pancreatic cancer tissues, Hint2 expression was low and related to prognosis. Up-regulation of Hint2 triggered apoptosis, and it could sensitize pancreatic cancer cells to gemcitabine-induced apoptosis [8]. In hepatocellular carcinoma, Hint2 was down-regulated, and low Hint2 expression predicted earlier tumor recurrence [4]. In colorectal carcinoma, Hint2 down-regulation promoted migration and metastasis [5].

In conclusion, Hint2 plays essential roles in multiple biological processes, especially those related to mitochondrial function. Studies using gene knockout or overexpression mouse models have revealed its significance in cardiovascular diseases, diabetes-related kidney diseases, and various cancers. These findings provide potential therapeutic targets for treating these diseases.