CLUH, also known as clustered mitochondria homolog, is a cytosolic RNA-binding protein. It plays essential roles in regulating mitochondrial function, metabolism, and cell cycle progression. CLUH binds to mRNAs encoding mitochondrial proteins, thereby regulating their translation, stability, and localization, which is crucial for mitochondrial biogenesis, oxidative phosphorylation, and other metabolic pathways [1,5,6,7,8,9].

In KO mouse models, CLUH-deficient cells show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways, failing to grow during G1 and progressing faster through the cell cycle, indicating dysregulated matching of growth, metabolism, and cell cycling [1]. In axons of motoneurons, lack of CLUH affects the abundance of target mRNAs and corresponding mitochondrial proteins, leading to ATP deficits in the growth cone and causing peripheral neuropathy and motor deficits [2]. In macrophages, reduced CLUH expression enhances mitochondrial ROS production, reduces mitophagy and lysosomal function, and exacerbates colitis in a mouse model [3]. Depletion of CLUH in Drosophila results in mitochondrial elongation due to its role in promoting recruitment of Drp1 to mitochondria for fission [4].

In conclusion, CLUH is vital for coupling mitochondrial metabolism to cell cycle progression, maintaining functional mitochondria in axons, regulating inflammation, and controlling mitochondrial fission. The study of CLUH-KO models has provided significant insights into its role in diseases such as ulcerative colitis, peripheral neuropathy, and dysregulated cell growth and metabolism.