A recent study by David Friedman and colleagues provides new insight into the mechanisms by which apolipoprotein L1 (APOL1) risk variants injure kidney cells. “These variants were identified almost 10 years ago, but we still don’t have a good understanding of how they increase the risk of kidney disease,” says Friedman. “There is also surprisingly little consensus on how the behaviour of the risk variants differs from that of the non-risk variants with respect to trafficking patterns or binding partners.”

To investigate the molecular behaviour of APOL1, the researchers used inducible cell lines that stably expressed either the risk or non-risk variants. They report that all of these variants translocate into mitochondria via the same import pathway and that blocking this pathway abrogates APOL1 risk variant-mediated cell death.

The researchers also show that once inside the mitochondria, the risk variants oligomerize to form multimers, whereas the non-risk variant remains monomeric. Both the risk and non-risk variants bind to components of the mitochondrial permeability transition pore, but only the risk variants activate pore opening, which leads to cell death.

“When comparing the risk and non-risk variants, the trafficking patterns and binding partners are similar, but the actions at the pore are different,” summarizes Friedman. “The difference in how the pore responds to APOL1 risk and non-risk variants may help to explain how the risk variants cause kidney disease.” The researchers now plan to investigate the effects of APOL1 variants in vivo. “Just as the risk variants are associated with different types of kidney disease, they may cause disease by different mechanisms, so we don’t think that opening of the pore is necessarily the only mechanism at work in APOL1 kidney disease,” says Friedman.