BLTP1-dependent phospholipid efflux prevents mitochondrial lipid overload and apoptosis at FKBP8-tethered ER-mitochondrial contact

Maintenance of mitochondrial phospholipid homeostasis is critical for organellar function and cell survival, yet mechanisms enabling phospholipid efflux from mitochondria remain undefined. We identify BLTP1 as a phospholipid transporter that exports phospholipids from mitochondria to maintain lipid homeostasis. The outer mitochondrial membrane protein FKBP8 recruits BLTP1 to ER-mitochondrial contact sites, establishing a dedicated lipid export pathway. BLTP1 deficiency triggers pathological accumulation of phosphatidic acid (PA), phosphatidylglycerol (PG), and cardiolipin (CL) within mitochondria. This lipid overload is associated with elevation of mitochondrial reactive oxygen species (ROS), bioenergetic dysfunction, and apoptosis. Critically, depleting intramitochondrial lipid transfer proteins (e.g., PRELID1) or enzymes in the CL synthesis pathway (e.g., PTPMT1, CRLS1) prevents apoptosis caused by BLTP1 deficiency. Our findings defines a BLTP1-FKBP8-dependent mechanism for mitochondrial phospholipid efflux that is essential for mitochondrial function and cell survival.