**1. Introduction**

In the United States, geographic atrophy in dry AMD (Age-related Macular Degeneration) is a primary cause of vision loss in the elderly [1], and it has limited treatment options compared to those available for wet AMD [2,3]. Among the wide variety of factors that are instrumental in the etiology and pathogenesis of AMD, mitochondrial damage in the Retinal Pigment Epithelium (RPE), leading to RPE dysfunction, contributes significantly. AMD mitochondria are fragmented, have a higher number of lesions, altered ATP synthase activity, as well as compromised protein expression and nuclear-encoded protein import [4–6]. Furthermore, as confirmed by ATAC-sequencing, chromatin accessibility is decreased significantly in the RPE in AMD retinas [7].

The human mitochondrial genome is ~16.5 kilobases, circular, double-stranded, and consists of 37 genes that code for 13 proteins of the respiratory chain complexes. These 13 proteins are a part of the electron transport chain and aid in oxidative metabolism and ATP production [8,9]. Some of the critical functions of mitochondria include, but are not limited to, ATP production via respiration, promoting thermogenesis via proton leak, regulation of cellular metabolism and calcium signaling, ROS generation, regulation of apoptosis, ion homeostasis, and heme synthesis [10]. The retina is a part of the central nervous system and is one of the highest energy-demanding tissues in the human body. Glycolysis in the cytosol and mitochondrial oxidative phosphorylation are the two primary sources of energy, i.e., ATP (adenosine triphosphate) generation. Retinal neurons derive their energy mostly from oxidative phosphorylation, which has a substantially higher ATP yield than glycolysis [11]. Unmet retinal energy demand puts the retinal neurons at a high risk of cell death that in turn causes impairment or loss of vision [12]. Mitochondrial function declines with age as a result of accumulated mtDNA damage/mutations [13]. The majority of proteins that support mitochondrial health and function are encoded by the nuclear genome. Therefore, coordinated regulation of mitochondrial and nuclear gene expression is essential to maintain cellular homeostasis [14]. Mammalian mitochondrial retrograde signaling, i.e., transmission of information from the mitochondria to the nucleus, is mediated

by G-Protein Pathway Suppressor 2 (GPS2), which also functions as a transcriptional activator of nuclear-encoded mitochondrial genes. GPS2-regulated direct translocation from the mitochondria to the nucleus is essential for the transcriptional activation of a nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis [15].

The mitochondrial genome encodes 22 tRNAs and two ribosomal RNAs, i.e., 12S rRNA and 16S rRNA, both of which are essential in synthesis of mitochondrial proteins. The 12S rRNA gene is 954 base pairs (bp) in length and spans 648–1601 bp of the mtDNA; it occupies 1/16 of the entire mtDNA and has 297 nucleotide substitutions, which account for 31% of the 12S rRNA gene. Furthermore, the 16S rRNA gene is 1559 bp long, spanning 1671–3229 bp of the mtDNA; it occupies 1/10 of the entire mtDNA and has 413 nucleotide substitutions, which account for 25% of the 16S rRNA gene [16]. Both 16S rRNA and 12S rRNA genes carry ORFs (Open Reading Frames) that encode mitochondrial-derived peptides.
