2025/06/25 by Etienne Pays · 1 voice
Immunology and Microbiology · Medicine · #Atherosclerosis and Cardiovascular Diseases #Cholesterol and Lipid Metabolism #Renal Diseases and Glomerulopathies
paper · doi:10.4103/regenmed.regenmed-d-25-00027
openalex publication_date 2025/06/25 · openalex created_date 2025/10/10 · openalex updated_date 2026/05/21
This review details the structure and functions of three members of the human apolipoprotein (APOL) family, namely, APOL1, APOL2, and APOL3. APOL1 and APOL3 are selectively induced by type I interferon-mediated inflammation. APOL1 is associated with factors that drive Golgi-derived vesicles to mitochondrion‒endoplasmic reticulum contact sites. This trafficking is induced by type I interferon to initiate mitophagy or apoptosis, which are crucial mitochondrial repair mechanisms in response to inflammatory damage. APOL3 is in a trimeric complex that controls the synthesis of the membrane phospholipid phosphatidylinositol-4-phosphate at the Golgi. When delocalized with APOL1 at mitochondrion‒endoplasmic reticulum contact sites following inflammation, PI(4)P kinase-B activity induces mitochondrial membrane fission for mitophagosome formation, and APOL3 promotes membrane fusion between mitophagosomes and endolysosomes to complete mitophagy. Thus, APOL1 and APOL3 control inflammation-linked vesicular trafficking and mitochondrial membrane dynamics, respectively. Chronic kidney disease can result from either the expression of APOL1 C-terminal variants or APOL3 deletion. Depending on inflammation, APOL1-mediated kidney disease, termed APOL1 nephropathy, is associated with two levels of podocyte cytopathology (hit 1 and hit 2). Both pathology levels involve actomyosin modifications, mitochondrial dysfunctions, and stress signaling, but inflammation-linked hit 2 is characterized by increased severity. Different C-terminal APOL1 variants, such as the G1 or G2 variants that allow humans to resist infection by pathogenic African trypanosomes, exhibit increased hydrophobicity, likely due to structural unfolding. These variants display increased interaction with APOL3, inhibiting APOL3 functions and mimicking experimental or natural APOL3 deletion. Thus, hit 1 may result from the inactivation of APOL3 membrane remodeling activities. Hit 2 is due to increased podocyte surface cation fluxes, which induce cytotoxicity through stress signaling. Two models can account for hit 2: either secreted G1 or G2 generates cation channels at the podocyte surface, or these variants activate existing cholesterol-dependent cation channels. In this review, I argue in favor of the second model. The closest APOL1 homolog, APOL2, can be considered another C-terminal variant. Accordingly, increased APOL2 expression induced by transforming growth factor-β1 could cause liver fibrosis and modulate gut mucosal immunity through exocytotic trafficking of vesicles carrying inactivated APOL3. APOL2 may also be involved in antigen cross-presentation and the apoptosis of dendritic cells via membrane permeabilization resulting from altered membrane fission-fusion by APOL3. In conclusion, through their basic functions in membrane remodeling, APOLs 1–3 are involved in various processes linked to cellular activation by either type I interferon or transforming growth factor-β1. In addition to APOL1-mediated kidney disease and liver fibrosis, other APOL-related diseases await discovery.