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bioRxiv · 10.1101/2021.08.16.456582

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

Wang, H.·Wang, L.·Yi, S.·Zhang, S.·Ho, M.
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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.

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Wang, H., Wang, L., Yi, S., Zhang, S., Ho, M.. 2021-08-17. SNARE-dependent mitochondria-lysosome contacts regulate glial mitochondrial dynamics and dopaminergic neuron survival. https://doi.org/10.1101/2021.08.16.456582

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