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.

线粒体 DNA (mtDNA) 功能障碍和 mtDNA 单倍群变异在年龄相关性黄斑变性 (AMD) 的病因学中发挥着关键作用。本研究检查了具有 U、K 和 J mtDNA 单倍群的 AMD ARPE-19 传递软骨细胞对线粒体靶向 PU-91 药物治疗的反应。 PU-91 通过上调 PGC-1α（过氧化物酶体增殖物激活受体-γ 共激活剂 (PGC)-1α）发挥其细胞保护作用，PGC-1α 是线粒体生物合成途径的主要调节因子。 PU-91 药物的作用是通过基于细胞的测定和基因表达分析来确定的。我们的研究表明，具有不同 mtDNA 单倍群（即 U、K、J 单倍群）的 AMD cybrids 对 PU-91 药物治疗的反应不同； PU-91 药物可以增加活细胞数量，改善线粒体健康，并全面保护 AMD 细胞免受氧化应激，无论其单倍群变异如何。这项研究表明，mtDNA 单倍群可能导致 AMD cybrid 细胞在体外对 PU-91 药物的差异反应，也可能影响 AMD 患者对药物治疗的反应。