PDZD8 is a multifunctional endoplasmic reticulum (ER)-anchored protein that serves as a molecular tether organizing inter-organellar membrane contact sites. Primary to its function, PDZD8 mediates ER-mitochondria tethering through direct interaction with the mitochondrial outer membrane protein FKBP8, forming a dynamic tethering complex 1. This tethering is essential for calcium homeostasis, enabling ER-to-mitochondrial Ca²⁺ transfer critical for regulating dendritic Ca²⁺ dynamics in neurons 2. Mechanistically, PDZD8 undergoes phase separation via its intrinsically disordered region to create condensates that act as adhesive frameworks maintaining inter-organellar proximity 3. Beyond calcium signaling, PDZD8 functions as a lipid transfer protein, mediating lipid movement between organelles. It acts as a lysosomal vacuolator by sensing lysosomal phosphatidylserine and cholesterol to regulate osmotic membrane expansion 4, and promotes autophagy at ER-lysosome contacts during activity-dependent synaptic growth 5. Additionally, PDZD8 serves as an AMPK substrate that regulates glutaminolysis by promoting GLS1 activation during glucose shortage 6. Disease relevance: elevated PDZD8 expression in pancreatic β-cells increases MAM formation and mitochondrial calcium overload, promoting β-cell apoptosis in diabetes 7. PDZD8 mutations are associated with intellectual developmental disorder with autism and dysmorphic facies, highlighting its critical role in neuronal development.