PDZD8, short for PDZ domain containing 8, is an endoplasmic reticulum (ER) transmembrane protein. It serves as a crucial tether between the ER and mitochondria, regulating Ca²⁺ dynamics [2]. PDZD8 is also involved in lipid transfer processes at membrane contact sites, influencing activities such as autophagy, lysosome maturation, and neurite outgrowth [3,4,5]. Moreover, it participates in metabolic regulation, with the AMPK-PDZD8-GLS1 axis promoting glutaminolysis during glucose shortage [1].

PDZD8-KO mice exhibit abnormal accumulation of cholesteryl esters in the brain due to impaired lipophagy, along with behavioral abnormalities related to emotion, cognition, and adaptation [4]. In humans, homozygous loss-of-function mutations in PDZD8 are associated with syndromic intellectual disability with autistic features [6]. In SIH rats, PDZD8 dysregulation in the rostral ventrolateral medulla disrupts mitochondrial functions, leading to neuronal hyperexcitation and increased blood pressure [7].

In summary, PDZD8 is essential for maintaining organelle contacts, regulating lipid metabolism, Ca²⁺ dynamics, and autophagy. The study of PDZD8-KO mouse models has revealed its significant roles in cognitive function, lipid metabolism in the brain, and stress-induced hypertension, providing insights into the pathophysiology of related diseases.

References:

1. Li, Mengqi, Wang, Yu, Wei, Xiaoyan, Zhang, Chen-Song, Lin, Sheng-Cai. 2024. AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine. In Cell research, 34, 683-706. doi:10.1038/s41422-024-00985-6. https://pubmed.ncbi.nlm.nih.gov/38898113/

2. Hirabayashi, Yusuke, Kwon, Seok-Kyu, Paek, Hunki, Pon, Liza A, Polleux, Franck. . ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons. In Science (New York, N.Y.), 358, 623-630. doi:10.1126/science.aan6009. https://pubmed.ncbi.nlm.nih.gov/29097544/

3. Thakur, Rajan S, O'Connor-Giles, Kate M. 2023. PDZD8 promotes autophagy at ER-Lysosome contact sites to regulate synaptogenesis. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.10.30.564828. https://pubmed.ncbi.nlm.nih.gov/37961523/

4. Kurihara, Yuji, Mitsunari, Kotone, Mukae, Nagi, Miyakawa, Tsuyoshi, Shirane, Michiko. 2023. PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain. In Molecular brain, 16, 11. doi:10.1186/s13041-023-01002-4. https://pubmed.ncbi.nlm.nih.gov/36658656/

5. Gao, Yuan, Xiong, Juan, Chu, Qing-Zhu, Ji, Wei-Ke. 2021. PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth. In Journal of cell science, 135, . doi:10.1242/jcs.255026. https://pubmed.ncbi.nlm.nih.gov/33912962/

6. Al-Amri, Ahmed H, Armstrong, Paul, Amici, Mascia, Inglehearn, Chris F, Clapcote, Steven J. 2022. PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies. In Biological psychiatry, 92, 323-334. doi:10.1016/j.biopsych.2021.12.017. https://pubmed.ncbi.nlm.nih.gov/35227461/

7. Liu, Tianfeng, Wang, Linping, Chen, Gaojun, Zhang, Shuai, Du, Dongshu. 2023. PDZD8-mediated endoplasmic reticulum-mitochondria associations regulate sympathetic drive and blood pressure through the intervention of neuronal mitochondrial homeostasis in stress-induced hypertension. In Neurobiology of disease, 183, 106173. doi:10.1016/j.nbd.2023.106173. https://pubmed.ncbi.nlm.nih.gov/37247681/