We report that PU-91, an FDA-approved drug, promotes mitochondrial-stabilization, PGC-1α upregulation, cytoprotection of AMD ARPE-19 transmitochondrial cybrid cells by preserving mitochondrial health, reducing apoptotic cell loss, and inducing upregulation of the MDP-coding MT-RNR2 gene. Here, PPARGC1A is linked to age-related macular degeneration.