APOL1 Kidney-Risk Variants Induce Mitochondrial Fission

Lijun Ma*, Hannah C Ainsworth, James A Snipes, Mariana Murea, Young A Choi, Carl D Langefeld, John S Parks, Manish S Bharadwaj, Jeff W Chou, Ashok K Hemal, Snezana Petrovic, Ann L Craddock, Dongmei Cheng, Gregory A Hawkins, Lance D Miller, Pamela J Hicks, Moin A Saleem, Jasmin Divers, Anthony J A Molina, Barry I Freedman*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)
32 Downloads (Pure)


Introduction: APOL1 G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of APOL1 and elucidate potential mechanisms in APOL1-nephropathy.

Methods: A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.

Results: APOL1 genotypes did not alter APOL1 expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to BAK1 was a trans eQTL for APOL1 and a cis eQTL for BAK1; APOL1 and BAK1 were co-expressed in cells. BAK1 knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on APOL1 expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various APOL1 genotypes. Mitochondria in APOL1 wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing APOL1 G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.

Conclusion: Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in APOL1-nephropathy.

Original languageEnglish
Pages (from-to)891-904
Number of pages14
JournalKidney international reports
Issue number6
Early online date30 Mar 2020
Publication statusPublished - 4 Jun 2020

Bibliographical note

© 2020 International Society of Nephrology. Published by Elsevier Inc.


  • African Americans
  • APOL1
  • chronic kidney disease
  • FSGS
  • mitochondria


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