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Genet."],"abstract":"<jats:p>\n                    Polymorphisms in the Apolipoprotein L1 (\n                    <jats:italic>APOL1<\/jats:italic>\n                    ) gene are common in ancestrally African populations, and associate with kidney injury and cardiovascular disease. These risk variants (RV) provide an advantage in resisting\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    , the causal agent of African trypanosomiasis, and are largely absent from non-African genomes. Clinical associations between the\n                    <jats:italic>APOL1<\/jats:italic>\n                    high risk genotype (HRG) and disease are stronger in those with comorbid infectious or immune disease. To understand the interaction between cytokine exposure and\n                    <jats:italic>APOL1<\/jats:italic>\n                    cytotoxicity, we established human umbilical vein endothelial cell (HUVEC) cultures representing each\n                    <jats:italic>APOL1<\/jats:italic>\n                    genotype. Untreated HUVECs were compared to IFN\u0263-exposed; and\n                    <jats:italic>APOL1<\/jats:italic>\n                    expression, mitochondrial function, lysosome integrity, and autophagic flux were measured. IFN\u0263 increased median\n                    <jats:italic>APOL1<\/jats:italic>\n                    expression across all genotypes 22.1 (8.3 to 29.8) fold (p=0.02). Compared to zero risk variant-carrying HUVECs (0RV), HUVECs carrying 2 risk variant copies (2RV) showed both depressed baseline and maximum mitochondrial oxygen consumption (p&amp;lt;0.01), and impaired mitochondrial networking on MitoTracker assays. These cells also demonstrated a contracted lysosomal compartment, and an accumulation of autophagosomes suggesting a defect in autophagic flux. Upon blocking autophagy with non-selective lysosome inhibitor, hydroxychloroquine, autophagosome accumulation between 0RV HUVECs and untreated 2RV HUVECs was similar, implicating lysosomal dysfunction in the HRG-associated autophagy defect. Compared to 0RV and 2RV HUVECs, HUVECs carrying 1 risk variant copy (1RV) demonstrated intermediate mitochondrial respiration and autophagic flux phenotypes, which were exacerbated with IFN\u0263 exposure. Taken together, our data reveal that IFN\u0263 induces\n                    <jats:italic>APOL1<\/jats:italic>\n                    expression, and that each additional RV associates with mitochondrial dysfunction and autophagy inhibition. IFN\u0263 amplifies this phenotype even in 1RV HUVECs, representing the first description of\n                    <jats:italic>APOL1<\/jats:italic>\n                    pathobiology in variant heterozygous cell cultures.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2022.769936","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T02:18:30Z","timestamp":1664245110000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["APOL1 variant-expressing endothelial cells exhibit autophagic dysfunction and mitochondrial stress"],"prefix":"10.3389","volume":"13","author":[{"given":"Ashira","family":"Blazer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzhi","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin Paul","family":"Schlegel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda","family":"Algasas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill P.","family":"Buyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Cadwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Heffron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Xia","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpi","family":"Mehta-Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Niewold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Rasmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Clancy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.freeradbiomed.2021.12.312","article-title":"An investigation of different intracellular parameters for Inborn Errors of Metabolism: Cellular stress, antioxidant response and autophagy","volume":"179","author":"Acar","year":"2021","journal-title":"Free Radic. 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