Ip6k3, inositol hexakisphosphate kinase 3, is an enzyme that generates inositol pyrophosphates. These molecules regulate diverse cellular functions, and the enzyme is involved in pathways related to metabolism, lifespan regulation, and neuronal function [2,3]. Its study using genetic models like knockout mice has provided insights into its physiological role.

In Ip6k3 knockout mice, there are lower blood glucose, reduced insulin, decreased fat mass, lower body weight, and extended lifespan, suggesting its role in metabolic control and lifespan regulation [2]. The knockout mice also display abnormal Purkinje cell structure and synapse number in the cerebellum, leading to deficits in motor learning and coordination, indicating its importance in neuronal function [4]. Deletion of Ip6k3 causes defects in cell motility and neuronal dendritic growth, eventually leading to brain malformations [5]. Additionally, a SNP of Ip6K3 previously associated with increased risk of late-onset Alzheimer's disease (LOAD) increased the chance to become long-lived [1].

In conclusion, Ip6k3 plays essential roles in metabolic regulation, lifespan determination, and neuronal function, especially in cerebellar Purkinje cells. The study of Ip6k3 knockout mouse models has provided valuable insights into its functions in these biological processes and its potential associations with diseases like LOAD.

References:

1. Dato, Serena, Crocco, Paolina, De Rango, Francesco, Rose, Giuseppina, Passarino, Giuseppe. 2021. IP6K3 and IPMK variations in LOAD and longevity: Evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival. In Mechanisms of ageing and development, 195, 111439. doi:10.1016/j.mad.2021.111439. https://pubmed.ncbi.nlm.nih.gov/33497757/

2. Moritoh, Yusuke, Oka, Masahiro, Yasuhara, Yoshitaka, Fuse, Hiromitsu, Tozawa, Ryuichi. 2016. Inositol Hexakisphosphate Kinase 3 Regulates Metabolism and Lifespan in Mice. In Scientific reports, 6, 32072. doi:10.1038/srep32072. https://pubmed.ncbi.nlm.nih.gov/27577108/

3. Chakkour, Mohamed, Greenberg, Miriam L. 2024. Insights into the roles of inositol hexakisphosphate kinase 1 (IP6K1) in mammalian cellular processes. In The Journal of biological chemistry, 300, 107116. doi:10.1016/j.jbc.2024.107116. https://pubmed.ncbi.nlm.nih.gov/38403246/

4. Fu, Chenglai, Xu, Jing, Li, Ruo-Jing, Pletnikov, Mikhail V, Snyder, Solomon H. . Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 35, 11056-67. doi:10.1523/JNEUROSCI.1069-15.2015. https://pubmed.ncbi.nlm.nih.gov/26245967/

5. Rojas, Tomas, Cheng, Weiwei, Gao, Zhe, Snyder, Solomon H, Fu, Chenglai. 2019. Inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2. In Proceedings of the National Academy of Sciences of the United States of America, 116, 3278-3287. doi:10.1073/pnas.1817001116. https://pubmed.ncbi.nlm.nih.gov/30718399/