VAMP7-dependent mitochondria-lysosome contacts regulate glial mitochondrial dynamics and dopaminergic neuron survival

Abstract

Disrupted mitochondrial dynamics in neurons are linked to neurodegenerative diseases, but their regulation in glia remains poorly understood. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation related to altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, resulting in increased ROS activity, lipid droplet accumulation, and dopaminergic (DA) neuron degeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GAP-dead TBC1D15-17{Delta}GAP phenocopies the mitochondrial defects, while GDP-bound Rab7^T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a new role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.