Differential responses of AMD mitochondrial DNA haplogroups to PU-91, a mitochondria-targeting drug

Abstract

Mitochondrial DNA (mtDNA) dysfunction and variation in mtDNA haplogroups play a key role in the etiology of Age-related Macular Degeneration (AMD). This study examined the response(s) of AMD ARPE-19 transmitochondrial cybrids having U, K, and J mtDNA haplogroups to treatment with a mitochondria-targeting PU-91 drug. PU-91 exerts its cytoprotective effects by upregulating PGC-1α (Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha) which is a primary regulator of the mitochondrial biogenesis pathway. The effects of PU-91 drug were determined using cell-based assays and gene expression analyses. Our study revealed that AMD cybrids with different mtDNA haplogroups i.e., U, K, J haplogroups respond differentially to PU-91 drug treatment; and that the PU-91 drug increases viable cell number, improves mitochondrial health, and protects AMD cybrids against oxidative stress across the board irrespective of their haplogroup variation. This study suggests that mtDNA haplogroups may contribute to the differential responses of AMD cybrid cells to PU-91 drug in vitro and may also influence AMD patients' responses to drug treatment.

Keywords: AMD; Age-related macular degeneration; Mitochondrial DNA haplogroup; PU-91.