SYNJ2BP is an outer mitochondrial membrane protein with a cytosolic PDZ domain that regulates cellular homeostasis through multiple interconnected pathways. Mechanistically, SYNJ2BP functions as a scaffolding protein that facilitates mitochondria-associated endoplasmic reticulum membrane (MAM) formation and stability 1. It forms complexes with ER-resident proteins like ESYT1 to maintain mitochondrial-ER contact sites, enabling calcium flux and lipid homeostasis 2. SYNJ2BP also regulates PINK1 mRNA localization at mitochondria through PDZ domain phosphorylation by AMPK, controlling mitochondrial quality control and mitophagy 3. Disease relevance varies by context. In intervertebral disc degeneration, SYNJ2BP loss disrupts MAM formation and mitochondrial zinc homeostasis, promoting cell senescence; restoration improves disc rejuvenation 1. In motor neuron diseases (SBMA and ALS4), elevated SYNJ2BP paradoxically increases pathological mitochondrial-ER contacts and mitochondrial dysfunction 4. In hepatocellular carcinoma, SYNJ2BP functions as a tumor suppressor through DLL4-Notch pathway activation 5, while in breast cancer it paradoxically promotes metastasis via PI3K/AKT signaling and PTEN degradation 6. In clear cell renal carcinoma, SYNJ2BP downregulation correlates with advanced disease, metastasis, and poor survival 7. These findings establish SYNJ2BP as a critical regulator of mitochondrial homeostasis with tissue-specific oncogenic or tumor-suppressive roles.