Apolipoproteins L1 and L3 control mitochondrial membrane dynamics

Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8. [Display omitted] •APOL3 controls the activity of the Golgi and mitochondrion membrane fission factor PI4KB•APOL1 allows APOL3 and PI4KB traffic to MERCSs, linked to mitochondrion fission and mitophagy•Through interaction with VAMP8, APOL3 promotes mitophagosome-endolysosome fusion•C-terminal APOL1 variants reduce the mitophagy flux through APOL3 and PI4KB inactivation Lecordier et al. report that APOL1 and APOL3 are involved in mitophagy. Whereas APOL1 mediates APOL3 and PI4KB traffic from the Golgi to MERCSs, APOL3 controls mitochondrial membrane fission and fusion through interactions with PI4KB and VAMP8, respectively. APOL1 C-terminal variants inhibit mitophagy through interference with APOL3 and PI4KB activities.