Apolipoproteins L1 and L3 Control Mitochondrial Membrane Dynamics

Apolipoproteins-L1 and -L3 (APOLs) are associated at the Golgi membrane with phosphatidylinositol-4-kinase-IIIB (PI4KB) and non-muscular-myosin-2A (NM2A). Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO) reduces Golgi 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 (NCS1) or calneuron-1 (CALN1). Both APOLs are present in Golgi-derived autophagy-related-protein-9A (ATG9A) vesicles, involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, decreasing the mitophagy flux through reduction of mitochondrial membrane fission and fusion, and triggering the production of reactive oxygen species. APOL1 and APOL3, respectively, bind to the mitophagy receptor prohibitin-2 (PHB2) and to the mitophagosome fusion protein vesicle-associated-membrane-protein-8 (VAMP8). While APOL1-PHB2 interaction may condition mitochondrial targeting of PI4KB, APOL3-VAMP8 interaction promotes membrane fusion, enhanced by cardiolipin. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.