APOL1 Kidney Risk Variants Induce Cell Death via Mitochondrial Translocation and Opening of the Mitochondrial Permeability Transition Pore
Abstract
Some variants in APOL1 are associated with high CKD rates in African Americans, but the molecular mechanism of disease remains elusive. Previous studies demonstrated that expression of APOL1 risk variants is associated with mitochondrial dysfunction. In this study, the authors show that import of APOL1 protein into mitochondria is essential for risk variant–mediated cytotoxicity, and map the APOL1 import pathway. They found that whereas APOL1 is mostly monomeric, risk variant APOL1 can form large oligomers and cause opening of the mitochondrial permeability transition pore, ultimately leading to cell death. This difference in propensity of different variants to oligomerize could help explain APOL1 risk variants’ gain-of-function biology despite a recessive mode of inheritance. Understanding APOL1 trafficking and interactions could help inform new therapeutic approaches.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 26, 2019
- Source ID
- 10.1681/asn.2019020114
Entities
People
- David J. Friedman
- Herbert Lannon
- Jia-yue Zhang
- Leny Dias
- Martin R. Pollak
- Seth L. Alper
- Shrijal S Shah
Organizations
- National Institutes of Health
- Nephcure Foundation
- United States Department of Defense
- Vertex Pharmaceuticals