Ian Trounce ^1* Neeru Vallabh ²

• ¹ Centre for Eye Research Australia, East Melbourne, Australia
• ² University of Liverpool, Liverpool, United Kingdom

The mitochondrial genome can replicate independently of nuclear DNA, and in humans there are usually 100-10,000 copies of mtDNA present in each cell [5]. The mitochondrial genome is organized as a circular, double-stranded DNA molecule and codes for only 37 genes across ~16,600 base pairs. Homoplasmy describes the state when all copies of mtDNA are mutant and heteroplasmy is the state when only a proportion of the mtDNA is mutant [5]. Theref ore, the coexistence of multiple mtDNA species (wild type mtDNA and mutated mtDNA variants) in a single cell or among cells within an individual makes mitochondrial diseases more complex and heterogeneous.The status of research into the pathogenesis and therapy of LHON is reviewed by Esmaeil et al (doi: 10.3389/f opht.2022.1077395). They provide an overview of the prevalence of LHON, the established mtDNA mutations in OXPHOS complex I genes, and ongoing controversies around bioenergetic insuf ficiency versus oxidative stress as primary pathogenic drivers. In addition, they consider the clinical course of the condition, along with other extraocular f eatures and potential links to neurological disorders. They conclude with an update on ongoing gene therapy trials in LHON which show promise. Some phenotypic similarities between classic mitochondrial optic neuropathies and glaucoma have prompted research into potential mitochondrial contributions to glaucoma, the most common optic neuropathy. Studies have found evidence of mitochondrial functional and mtDNA genetic contributions to glaucoma [2,6]. The report from Vallbona-Garcia et al (doi: 10.3389/fopht.2023.1309836) adds to this by showing that mtDNA D-loop homoplasmic variants appear to be increased in high tension glaucoma subjects with a higher percentage of those being in the 7S DNA within the HV1 region. As the mtDNA D-loop is noncoding but contains regions crucial to the regulation of mtDNA replication and transcription, they speculate that some of these variants may lead to mtDNA copy number depletion which this group has previously identified in this sub-group of glaucoma [7]. An improved understanding of changes in mitochondrial replication may be vital f or determining the role of treatments that target mitochondrial biogenesis as potential f uture strategies f or neuro -ophthalmological disorders.Ref lecting disparities in access to health care and participation in clinical studies, individuals of African ancestry have been underrepresented in retinal research as participants. Patients of African origin are disproportionately affected by primary open angle glaucoma (POAG) at all ages ; the prevalence of POAG in Af rican Americans is f ivefold higher than Caucasians. The biological mechanisms by which this group are disproportionately af f ected is poorly understood. Kuang et al (doi: 10.3389/f opht.2023.1267119) bring the current evidence of mtDNA analyses of Af rican ancestry glaucoma subjects into focus. African ancestry presents the largest diversity of mtDNA variation in humans, due to this continent being the source of human dispersal in prehistory. As such, this diversity requires large and caref ully matched cohorts f or genetic analysis. Kuang et al summarize the associations found to date, with non-L3 mtDNA L haplogroups showing higher prevalence in glaucoma subjects. The establishment of the Primary Open Angle Af rican American Glaucoma Genetics study (POAAGG) in the Philadelphia area has already uncovered new nuclear genetic loci associated with glaucoma risk in this population [8]; we eagerly await mtDNA analysis in this largest African ancestry population cohort to date. Some specialized retinal imaging technologies may be well suited to detecting mitochondrial dysfunction in vivo [9]. Among these, flavoprotein fluorescence (FPF) holds promise. Both NAD/H and FAD/H are key intermediaries of OXPHOS, and due to their intrinsic fluorescence, their measurement can provide information on mitochondrial metabolic alterations and oxidative stress. Ahsanuddin et al (doi: 10.3389/fopht.2023.1110501) show that current generation FPF retinal cameras can robustly discriminate diseased eyes with various retinal diseases associated with oxidative stress, including exudative macular degeneration, diabetic retinopathy and retinal vein occlusion. Imaging mitochondrial dysfunction in vivo using flavoprotein f luorescence may enable real-time, non-invasive assessment of cellular metabolic health, potentially leading to earlier detection and determining those at greater risk of progression. This technology holds great promise in parsing mitochondrial endophenotypes within diverse disease groupings such as glaucoma [10].Rombaut et al (doi: 10.3389/f opht.2023.1290465) go beyond the retinal ganglion cell to explore evidence for wider metabolic alterations in retinal glia cells in glaucoma. Retinal glial cells support and protect retinal ganglion cells by maintaining the structural integrity of the retina, regulating neurotransmitter levels, and managing the retinal environment to ensure proper visual function. They summarize evidence for alterations in glaucoma of the neuro -glia metabolic coupling, including in retinal Muller cells, microglia and astrocytes. The authors present an authoritative perspective on NAD balance, the lactate shuttle, glutamate handling and lipid shuttling roles of glia in support of retinal neurons, and how impacts on these cells may in turn inf luence neuronal health and survival where mitochondria sit as a central hub. Hence the retinal glial cells may also provide shared neuroprotective targets f or glaucoma treatment.Mitochondrial studies in ophthalmic diseases continue to gain momentum. The relative ease of access to the eye f or ocular samples, imaging and gene therapy puts retinal diseases at the f orefront of mitochondrial therapeutic development in neuroscience. The overlap of neurodegenerative brain and eye diseases, and mitochondrial dysfunction, promises to be a productive research focus. Mitochondrial are a central metabolic hub, and the added twist of having their own maternally inherited genome brings complexity to genetic analyses which are only recently being appreciated. The integration of mitochondrial genetics and f unction in neuro -ophthalmological research holds promise f or advancing our understanding and providing translational personalised treatments of these disorders.