Intracellular APOL1 Risk Variants Cause Cytotoxicity Accompanied by Energy Depletion

J Am Soc Nephrol. 2017 Nov;28(11):3227-3238. doi: 10.1681/ASN.2016111220. Epub 2017 Jul 10.


Population genetic approaches have uncovered a strong association between kidney diseases and two sequence variants of the APOL1 gene, called APOL1 risk variant G1 and variant G2, compared with the nonrisk G0 allele. However, the mechanism whereby these variants lead to disease manifestation and, in particular, whether this involves an intracellular or extracellular pool of APOL1 remains unclear. Herein, we show a predominantly intracellular localization of APOL1 G0 and the renal risk variants, which localized to membranes of the endoplasmic reticulum in podocyte cell lines. This localization did not depend on the N-terminal signal peptide that mediates APOL1 secretion into the circulation. Additionally, a fraction of these proteins localized to structures surrounding mitochondria. In vitro overexpression of G1 or G2 lacking the signal peptide inhibited cell viability, triggered phosphorylation of stress-induced kinases, increased the phosphorylation of AMP-activated protein kinase, reduced intracellular potassium levels, and reduced mitochondrial respiration rates. These findings indicate that functions at intracellular membranes, specifically those of the endoplasmic reticulum and mitochondria, are crucial factors in APOL1 renal risk variant-mediated cell injury.

Keywords: APOL1; endoplasmic reticulum; energy depletion; mitochondria; podocyte; renal risk variant.

MeSH terms

  • Apolipoprotein L1
  • Apolipoproteins* / analysis
  • Apolipoproteins* / genetics
  • Apolipoproteins* / physiology
  • Cells, Cultured
  • Endoplasmic Reticulum / chemistry
  • Energy Metabolism*
  • Genetic Variation
  • Humans
  • Lipoproteins, HDL* / analysis
  • Lipoproteins, HDL* / genetics
  • Lipoproteins, HDL* / physiology
  • Mitochondrial Membranes / chemistry
  • Risk Factors


  • APOL1 protein, human
  • Apolipoprotein L1
  • Apolipoproteins
  • Lipoproteins, HDL