biostudies-literatureZheng JTsinghua UniversityMinistry of Science and Technology of the People's Republic of ChinaNational Natural Science Foundation of Chinae54859https://www.ebi.ac.uk/biostudies/studies/S-EPMC9535754biostudies-literatureUnknown23(10)The hexameric AAA-ATPase valosin-containing protein (VCP) is essential for mitochondrial protein quality control. How VCP is recruited to mammalian mitochondria remains obscure. Here we report that UBXD8, an ER- and lipid droplet-localized VCP adaptor, also localizes to mitochondria and locally recruits VCP. UBXD8 associates with mitochondrial and ER ubiquitin E3 ligases and targets their substrates for degradation. Remarkably, both mitochondria- and ER-localized UBXD8 can degrade mitochondrial and ER substrates in cis and in trans. UBXD8 also associates with the TOM complex but is dispensable for translocation-associated degradation. UBXD8 knockout impairs the degradation of the pro-survival protein Mcl1 but surprisingly sensitizes cells to apoptosis and mitochondrial stresses. UBXD8 knocEMBO reportsUBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.PMC953575431871346Zheng JYang JCao YJiang HfalseUBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.The hexameric AAA-ATPase valosin-containing protein (VCP) is essential for mitochondrial protein quality control. How VCP is recruited to mammalian mitochondria remains obscure. Here we report that UBXD8, an ER- and lipid droplet-localized VCP adaptor, also localizes to mitochondria and locally recruits VCP. UBXD8 associates with mitochondrial and ER ubiquitin E3 ligases and targets their substrates for degradation. Remarkably, both mitochondria- and ER-localized UBXD8 can degrade mitochondrial and ER substrates in cis and in trans. UBXD8 also associates with the TOM complex but is dispensable for translocation-associated degradation. UBXD8 knockout impairs the degradation of the pro-survival protein Mcl1 but surprisingly sensitizes cells to apoptosis and mitochondrial stresses. UBXD8 knoc2022-01-01T00:00:00Z2022 Oct2026-07-14T15:36:41.641Z2025-04-04T20:06:59.449ZS-EPMC95357543597973310.15252/embr.202254859