Cluh-flox Mouse

CLUH, also known as clustered mitochondria homolog, is a cytosolic RNA-binding protein. It plays a crucial role in regulating mitochondrial function, metabolism, and cell cycle progression. CLUH binds to mRNAs encoding mitochondrial proteins, influencing their translation, stability, and localization, which is essential for maintaining normal mitochondrial biogenesis and function. It is involved in pathways such as oxidative phosphorylation, mTORC1 signaling, and mitochondrial fission, and its function is vital for normal cell growth, development, and homeostasis [1,4,5,7,9]. Genetic models, especially knockout (KO) mouse models, are valuable tools for studying CLUH's function.

In KO mouse models and other loss-of-function experiments, several key findings have emerged. In cells lacking CLUH, astrin levels decrease, mTORC1 signaling increases, but cells cannot sustain anaplerotic and anabolic pathways, resulting in dysregulated growth, metabolism, and cell cycling [1]. In motoneurons, the absence of CLUH leads to ATP deficits in the growth cone, peripheral neuropathy, and motor deficits due to its role in maintaining functional mitochondria and axonal translation [2]. In human macrophages, reduced CLUH expression enhances mitochondrial ROS production, impairs mitophagy and lysosomal function, and exacerbates inflammation, as seen in ulcerative colitis pathogenesis [3]. In Drosophila and mammalian cells, depletion of CLUH causes mitochondrial elongation due to its role in promoting Drp1 recruitment to mitochondria for fission [4]. In adipocytes, Cluh depletion impairs proper differentiation and reduces mitochondrial respiration [6]. In hepatocytes, without CLUH, a mitophagy block causes mitochondrial clustering [5]. In general, CLUH-knockout cells show OXPHOS defects, a metabolic shift towards glucose dependency, and alterations in amino acid and lipid metabolism [8].

In conclusion, CLUH is essential for coupling mitochondrial metabolism with cell cycle progression, maintaining functional mitochondria in neurons, regulating inflammation in macrophages, controlling mitochondrial fission, promoting adipogenesis, and coordinating metabolic adaptation in hepatocytes. The study of CLUH KO/CKO mouse models has significantly contributed to understanding its role in diseases such as ulcerative colitis, peripheral neuropathy, and potentially others related to mitochondrial and metabolic dysfunctions.