Intracellular APOL1 risk variants cause cytotoxicity accompanied by energy depletion

Daniel Granado, Daria Müller, Vanessa Krausel, Etty Kruzel-Davila, Christian Schuberth, Melanie Eschborn, Roland Wedlich-Söldner, Karl Skorecki, Hermann Pavenstädt, Ulf Michgehl, Thomas Weide

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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 thatmediates 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 AMPactivated 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.

Original languageEnglish
Pages (from-to)3227-3238
Number of pages12
JournalJournal of the American Society of Nephrology : JASN
Issue number11
StatePublished - Nov 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 by the American Society of Nephrology.


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