APOL1 kidney-risk variants induce mitochondrial fission

Lijun Ma, Moin Saleem, et al.

Research output: Contribution to journalArticle (Academic Journal)

Abstract

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 Americans. 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 poly IC-stimulated renal tubule cells revealed that 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, while 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, while 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
JournalKidney International
Publication statusAccepted/In press - 8 Feb 2020

Keywords

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

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