{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:12:55Z","timestamp":1792548775813,"version":"4.5.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-14-1-0333"],"award-info":[{"award-number":["W81XWH-14-1-0333"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MD007898"],"award-info":[{"award-number":["MD007898"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007519","name":"NephCure Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007519","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011022","name":"Vertex Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011022","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,12]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Some variants in\n APOL1<\/jats:italic>\n are associated with high CKD rates in African Americans, but the molecular mechanism of disease remains elusive. Previous studies demonstrated that expression of\n APOL1<\/jats:italic>\n risk variants is associated with mitochondrial dysfunction. In this study, the authors show that import of APOL1 protein into mitochondria is essential for risk variant\u2013mediated cytotoxicity, and map the APOL1 import pathway. They found that whereas APOL1 is mostly monomeric, risk variant APOL1 can form large oligomers and cause opening of the mitochondrial permeability transition pore, ultimately leading to cell death. This difference in propensity of different variants to oligomerize could help explain\n APOL1<\/jats:italic>\n risk variants\u2019 gain-of-function biology despite a recessive mode of inheritance. Understanding APOL1 trafficking and interactions could help inform new therapeutic approaches.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n Genetic Variants in Apolipoprotein L1 (APOL1) are associated with large increases in CKD rates among African Americans. Experiments in cell and mouse models suggest that these risk-related polymorphisms are toxic gain-of-function variants that cause kidney dysfunction, following a recessive mode of inheritance. Recent data in trypanosomes and in human cells indicate that such variants may cause toxicity through their effects on mitochondria.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To examine the molecular mechanisms underlying\n APOL1<\/jats:italic>\n risk variant\u2013induced mitochondrial dysfunction, we generated tetracycline-inducible HEK293 T-REx cells stably expressing the\n APOL1<\/jats:italic>\n nonrisk G0 variant or\n APOL1<\/jats:italic>\n risk variants. Using these cells, we mapped the molecular pathway from mitochondrial import of APOL1 protein to APOL1-induced cell death with small interfering RNA knockdowns, pharmacologic inhibitors, blue native PAGE, mass spectrometry, and assessment of mitochondrial permeability transition pore function.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n We found that the APOL1 G0 and risk variant proteins shared the same import pathway into the mitochondrial matrix. Once inside, G0 remained monomeric, whereas risk variant proteins were prone to forming higher-order oligomers. Both nonrisk G0 and risk variant proteins bound components of the mitochondrial permeability transition pore, but only risk variant proteins activated pore opening. Blocking mitochondrial import of APOL1 risk variants largely eliminated oligomer formation and also rescued toxicity.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our study illuminates important differences in the molecular behavior of APOL1 nonrisk and risk variants, and our observations suggest a mechanism that may explain the very different functional effects of these variants, despite the lack of consistently observed differences in trafficking patterns, intracellular localization, or binding partners. Variant-dependent differences in oligomerization pattern may underlie APOL1\u2019s recessive, gain-of-function biology.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2019020114","type":"journal-article","created":{"date-parts":[[2019,9,26]],"date-time":"2019-09-26T16:44:22Z","timestamp":1569516262000},"page":"2355-2368","source":"Crossref","is-referenced-by-count":87,"title":["APOL1 Kidney Risk Variants Induce Cell Death via Mitochondrial Translocation and Opening of the Mitochondrial Permeability Transition Pore"],"prefix":"10.1681","volume":"30","author":[{"given":"Shrijal 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