TBC1D15 is a RAB7 GTPase-activating protein that regulates mitochondrial and lysosomal homeostasis through control of interorganellar contacts 1. Its primary function involves mediating RAB7 GTP hydrolysis at mitochondria-lysosome contact sites, promoting their untethering and enabling dynamic organellar communication 12. TBC1D15 recruits the mitochondrial fission protein Drp1 to contact sites via direct C-terminal interaction, facilitating asymmetrical mitochondrial fission and preserving mitochondrial function 3. Mechanistically, TBC1D15 acts through the FIS1/RAB7 cascade to regulate mitochondrial dynamics and mitophagy flux 2. Beyond mitochondrial fission, TBC1D15 interacts with PLIN5 to promote mitochondria-lipid droplet contacts, enhancing fatty acid β-oxidation 4, and regulates amino acid homeostasis at contact sites by maintaining active RAB7 5. Disease relevance is substantial: TBC1D15 levels decrease in myocardial ischemia/reperfusion injury and acute myocardial infarction, and overexpression provides cardioprotection by restoring mitochondrial function and reducing apoptosis 32. In Parkinson's disease, GBA1 dysfunction dysregulates TBC1D15-mediated contact untethering, disrupting mitochondrial distribution 6. Alzheimer's disease shows elevated microglial TBC1D15 that paradoxically inhibits protective autophagy 7. Additionally, TBC1D15 stabilizes NOTCH signaling to promote tumor-initiating cell self-renewal 8, suggesting oncogenic potential in certain contexts.