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Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER-mitochondrial interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting-associated protein 13D (VPS13D) in the negative regulation of ER-mitochondrial MCSs. VPS13D suppression results in extensive ER-mitochondrial tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in the mitochondrial morphology, mitochondrial cellular distribution and mitochondrial DNA synthesis. Together our results suggest that VPS13D negatively regulates the ER-mitochondrial MCSs partially through its interactions with VCP/p97.   [Media: see text]

VPS13D interacts with VCP/p97 and negatively regulates ER- mitochondrial interactions