ORP5 and ORP8 orchestrate LD biogenesis at MAMs. (1 and 2) The ORP5/8 complex localizes at MAM subdomains (1) where LDs originate (2). (3) During lipogenesis, ORP5 and ORP8 interact with seipin and regulate its recruitment to MAM subdomains enriched in PA phospholipid (3) to sustain proper LD biogenesis. Our data suggest that ORP5/8 could regulate lipid transport pathways across the mitochondria—MAM—LD junctions.