8.A.246.  The Peroxisome Proliferator-activated Receptor Gamma Coactivator 1-beta (PGC-1a) Family 

It plays a role as a stimulator of transcription factors and nuclear receptor activities (Kressler et al. 2002). It activates transcriptional activity of estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and glucocorticoid receptor in the presence of glucocorticoids, and may play a role in constitutive non-adrenergic-mediated mitochondrial biogenesis as suggested by increased basal oxygen consumption and mitochondrial number when overexpressed. May be involved in fat oxidation and non-oxidative glucose metabolism and in the regulation of energy expenditure. It induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. 

In mice, repression of Pgc-1α alone induced RPE and retinal degeneration and drusen-like deposits. In vitro inhibition of PGC1A by CRISPR-Cas9 gene editing in human retinal pigment epithelium (RPE) (ARPE19- PGC1A KO) affected the expression of genes responsible for lipid metabolism, fatty acid β-oxidation (FAO), fatty acid transport, low-density lipoprotein (LDL) uptake, cholesterol esterification, cholesterol biosynthesis, and cholesterol efflux (Zhou et al. 2024). Moreover, inhibition of PGC1A in RPE cells caused lipid droplet accumulation and lipid peroxidation. ARPE19-PGC1A KO cells also showed reduced mitochondrial biosynthesis, impaired mitochondrial dynamics and activity, reduced antioxidant enzymes, decreased mitochondrial membrane potential, loss of cardiolipin, and increased susceptibility to oxidative stress (Zhou et al. 2024). These data demonstrate the crucial role of PGC-1α in regulating lipid metabolism and provide n insight into the mechanisms involved in lipid and drusen accumulation in the RPE and retina during aging and AMD.  This may pave the way for developing novel therapeutic strategies targeting PGC-1α.