This study investigates whether reduced optic atrophy 1 (
) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) ...control mice, streptozotocin (STZ)-induced diabetic mice,
mice, and diabetic
mice were used in this study. 16 weeks after diabetes onset, retinas were assessed for Opa1 and Bax levels by Western blot analysis, and retinal networks were examined for acellular capillaries (AC) and pericyte loss (PL). Apoptotic cells were detected in retinal capillaries using TUNEL assay, and caspase-3 activity was assessed using fluorometric analysis. Opa1 expression was significantly downregulated in retinas of diabetic and
mice compared with those of WT mice. Inducing diabetes further decreased Opa1 expression in retinas of
mice. Increased cytochrome c release concomitant with increased level of pro-apoptotic Bax and elevated caspase-3 activity were observed in retinas of diabetic and
mice; the number of TUNEL-positive cells and AC/PL was also significantly increased. An additional decrease in the Opa1 level in retinas of diabetic
mice exacerbated the development of apoptotic cells and AC/PL compared with those of diabetic mice. Diabetes-induced Opa1 downregulation contributes, at least in part, to the development of retinal vascular lesions characteristic of DR.
Mitochondria are known to play an essential role in photoreceptor function and survival that enables normal vision. Within photoreceptors, mitochondria are elongated and extend most of the ...innersegment length, where they supply energy for protein synthesis and the phototransduction machinery in the outer segment, as well as acting as a calcium store. Here, we examined the arrangement of the mitochondria within the inner segment in detail using three-dimensional (3D) electron microscopy techniques and show they are tethered to the plasma membrane in a highly specialized arrangement. Remarkably, mitochondria and their cristae openings align with those of neighboring inner segments. The pathway by which photoreceptors meet their high energy demands is not fully understood. We propose this to be a mechanism to share metabolites and assist in maintaining homeostasis across the photoreceptor cell layer. In the extracellular space between photoreceptors, Müller glial processes were identified. Due to the often close proximity to the inner-segment mitochondria, they may, too, play a role in the inner-segment mitochondrial arrangement as well as metabolite shuttling. OPA1 is an important factor in mitochondrial homeostasis, including cristae remodeling; therefore, we examined the photoreceptors of a heterozygous Opa1 knockout mouse model. The cristae structure in the Opa1
+/− photoreceptors was not greatly affected, but the mitochondria were enlarged and had reduced alignment to neighboring inner-segment mitochondria. This indicates the importance of key regulators in maintaining this specialized photoreceptor mitochondrial arrangement.
Absorption of photon energy by neuronal mitochondria leads to numerous downstream neuroprotective effects. Red and near infrared (NIR) light are associated with significantly less safety concerns ...than light of shorter wavelengths and they are therefore, the optimal choice for irradiating the retina. Potent neuroprotective effects have been demonstrated in various models of retinal damage, by red/NIR light, with limited data from human studies showing its ability to improve visual function. Improved neuronal mitochondrial function, increased blood flow to neural tissue, upregulation of cell survival mediators and restoration of normal microglial function have all been proposed as potential underlying mechanisms of red/NIR light.
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Mitochondrial disease is among the most common form of inherited neurological disorder, with a minimum prevalence of 1:5000 and few if any effective treatments or cures. Mitochondria ...are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Mitochondrial dysfunction is seen in numerous diseases, including rare primary genetic mitochondrial diseases, many affecting the eye and vision and various common degenerative disorders. Mitochondrial dysfunction is implicated in the ageing process and also contributes to ischaemic cardiac disease and cancer. Mitochondrial dysfunction has been well documented in neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, glaucoma and age‐related macular degeneration. Consequently, it is now becoming a major target for new therapeutic development. To date, however, there have been few if any successes. The problems faced in addressing mitochondrial dysfunction range from identifying suitable targets to lack of methods that reliably transfect mitochondria. There may be huge potential in taking an advanced therapy medicinal products (ATMPs) approach, developing medicines for human use that are based on genes, tissues or cells. A novel approach in the literature is the transplantation of fully functional mitochondria directly into defective cells. Could this be the more generic solution that would address the diverse range of mitochondrial defects in disease?
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Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, affecting approximately 1 in 25 000 people. DOA has an insidious onset in early childhood. It ...presents typically with bilateral central painless vision loss, dyschromatopsia, and optic disc pallor due to gradual retinal ganglion cell (RGC) loss and optic nerve degeneration. 60%–70% of genetically confirmed DOA cases are associated with variants in OPA1. OPA1 is an ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and maintenance of bioenergetic output. Over 250 known pathogenic variants in OPA1 have been reported, with missense variants within the GTPase domain associated with an increased susceptibility to developing DOA plus (DOA+), a multisystemic syndromic form of the disease with extraocular features, including sensorineural hearing loss and ataxia. Current therapeutic options to treat DOA are limited. Idebenone has been shown to protect against visual loss in Leber's hereditary optic neuropathy (LHON). In DOA off ‐label retrospective series show some promise in some patients.
Animal models for OPA1 DOA, have been reported, including Drosophila, C elegans, Danio rerio and mouse models. They have cast light on some potential therapeutic modalities. Despite limitations, murine models of DOA are currently indispensable for understanding pathophysiology of disease, drug testing and development. They replicate many symptoms and signs of human disease. However, there are caveats. Chemically induced Complex I deficits are very toxic. Genetic models of mitochondrial mutation affect protein integrity and function and can cause severe pathologies. This is made more problematic if there is a need for aging the mouse to bring out the full phenotype. We shall review the mouse models and describe some features that aid or our understanding of pathophysiological mechanisms. Our research has characterized the earliest morphological changes as a progressive loss of synapses, dendrite retraction and RGC remodelling and loss of connectivity. In the DOA mouse Opa1+/− mouse (B6;C3‐Opa1Q285STOP), heterozygous Opa1+/− mice develop visual defects, on psychophysics (optokinetic response) and electrophysiology (VEP, PhNR), consistent with RGC dysfunction. There is depressed mitochondrial Complex I and IV activity. Visible structural changes and disrupted axon morphology in the optic nerve are seen. We have carried out a randomized, placebo‐controlled trial of the benzoquinone idebenone in our ADOA mouse, which revealed a limited therapeutic effect on RGC dendropathy and visual function.
It is apparent that there are large differences between the rodent and primate visual system. The fovea of the retina, a critical component for central vision is one of the only primate‐specific components of the mammalian nervous system and is thus, not found in rodent. For these reasons, there is a strong case to use human cells. We shall review data on induced human pluripotent stem cell (hiPSC) with OPA1 mutation, with or without differentiation to RGCs, as models, and on CRISPRCas9 correction of patient‐derived OPA1 iPSC lines.
Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the ...optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Photobiomodulation (PBM) with red light provided neuroprotection to RGCs when administered ex vivo to wild-type retinal explants. In the current study, we used aged (13–15-month-old) wild-type and heterozygous B6;C3-Opa1Q285STOP (Opa1+/−) mice, a model of ADOA exhibiting RGC dendropathy. These mice were pre-treated with 4 J/cm2 of 670 nm light for five consecutive days before the eyes were enucleated and the retinas flat-mounted into explant cultures for 0-, 8- or 16-h ex vivo. RGCs were imaged by confocal microscopy, and their dendritic architecture was quantified by Sholl analysis. In vivo 670 nm light pretreatment inhibited the RGC dendropathy observed in untreated wild-type retinas over 16 h ex vivo and inhibited dendropathy in ON-center RGCs in wild-type but not Opa1+/− retinas. Immunohistochemistry revealed that aged Opa1+/− RGCs exhibited increased nitrosative damage alongside significantly lower activation of NF-κB and upregulation of DJ-1. PBM restored NF-κB activation in Opa1+/− RGCs and enhanced DJ-1 expression in both genotypes, indicating a potential molecular mechanism priming the retina to resist future oxidative insult. These data support the potential of PBM as a treatment for diseases involving RGC degeneration.
Autosomal Dominant Optic Atrophy (ADOA) is an ophthalmological condition associated primarily with mutations in the
gene. It has variable onset, sometimes juvenile, but in other patients, the disease ...does not manifest until adult middle age despite the presence of a pathological mutation. Thus, individuals carrying mutations are considered healthy before the onset of clinical symptoms. Our research, nonetheless, indicates that on the cellular level pathology is evident from birth and mutant cells are different from controls. We argue that the adaptation and early recruitment of cytoprotective responses allows normal development and functioning but leads to an exhaustion of cellular reserves, leading to premature cellular aging, especially in neurons and skeletal muscle cells. The appearance of clinical symptoms, thus, indicates the overwhelming of natural cellular defenses and break-down of native protective mechanisms.
Purpose: To report three older male individuals, all homoplasmic for m.14484 T > C mutation in the ND6 gene, presenting onset of vision loss weeks‐months after covid vaccination. None reported a ...history of covid‐19 infection.Methods: All clinical data was extracted and reported here as a Case Series.Results: A 68 years old man (A) had a 3rd dose of BioNTech/Pfizer COVID‐19 vaccination on 1st Nov 2021. 10 days later his vision was 6/6 OD and 6/60 OS. By Dec 2021 VA was 6/36 OD and 6/60 OS. His nephew lost vision age of 18 years with LHON. In March 2022, visual acuities were HM OD and HM OS. In May 2022 visual acuity was HM OD, PL OS. He started on idebenone 300 mg tds.A 55 years old man (B) had a 1st dose Astra Zeneca COVID‐19 vaccination in mid Feb 2021. 12 days later, March 2021 he developed a Bell's Palsy and sensory neuropathy at the top of his legs, feet and upper arms, with difficulty walking. MRI showed enhanced optic nerves and enhanced lesions at C2. In April 2021, he lost vision in his right eye, followed by left eye in June 2021. By September 2021 vision was CF BEs. He started on idebenone 300 mg po tds. In May 2022 he was LogMAR @ 2 m 1.34 OD and MH OS.A 72 years old man (C) had his 2nd dose of BioNTech/Pfizer COVID‐19 vaccination in April 2021. In Sept 2021 he reported loss of vision in both eyes but could not date onset. He was the maternal cousin of individual B. In May 2022 vision was 3/60 OD CF OS. He started on idebenone 300 mg po tds.Conclusions: Adverse ocular events related to COVID‐19 vaccines are remarkable rare. There are >20 published case reports (~89 patients) of adverse ocular events within 28 days of COVID‐19 vaccination, with all three vaccines (Pfizer, AstraZeneca and Moderna). Reports incl. conjunctivitis, facial and abducens nerve palsy, CSR, uveitis, MEWDS, VKH, Graves' Disease, endothelial graft rejection, AAION and AZOOR. The role of vaccination in subsequent vision loss in those with underlying mitochondrial mutation is not clear.
Purpose: To report three older male individuals, all homoplasmic for m.14484 T > C mutation in the ND6 gene, presenting onset of vision loss weeks‐months after covid vaccination. None reported a ...history of covid‐19 infection.
Methods: All clinical data was extracted and reported here as a Case Series.
Results: A 68 years old man (A) had a 3rd dose of BioNTech/Pfizer COVID‐19 vaccination on 1st Nov 2021. 10 days later his vision was 6/6 OD and 6/60 OS. By Dec 2021 VA was 6/36 OD and 6/60 OS. His nephew lost vision age of 18 years with LHON. In March 2022, visual acuities were HM OD and HM OS. In May 2022 visual acuity was HM OD, PL OS. He started on idebenone 300 mg tds.
A 55 years old man (B) had a 1st dose Astra Zeneca COVID‐19 vaccination in mid Feb 2021. 12 days later, March 2021 he developed a Bell's Palsy and sensory neuropathy at the top of his legs, feet and upper arms, with difficulty walking. MRI showed enhanced optic nerves and enhanced lesions at C2. In April 2021, he lost vision in his right eye, followed by left eye in June 2021. By September 2021 vision was CF BEs. He started on idebenone 300 mg po tds. In May 2022 he was LogMAR @ 2 m 1.34 OD and MH OS.
A 72 years old man (C) had his 2nd dose of BioNTech/Pfizer COVID‐19 vaccination in April 2021. In Sept 2021 he reported loss of vision in both eyes but could not date onset. He was the maternal cousin of individual B. In May 2022 vision was 3/60 OD CF OS. He started on idebenone 300 mg po tds.
Conclusions: Adverse ocular events related to COVID‐19 vaccines are remarkable rare. There are >20 published case reports (~89 patients) of adverse ocular events within 28 days of COVID‐19 vaccination, with all three vaccines (Pfizer, AstraZeneca and Moderna). Reports incl. conjunctivitis, facial and abducens nerve palsy, CSR, uveitis, MEWDS, VKH, Graves' Disease, endothelial graft rejection, AAION and AZOOR. The role of vaccination in subsequent vision loss in those with underlying mitochondrial mutation is not clear.
Retinal involvement in mitochondrial disease is a variable feature of mitochondrial dysfunction. The retinal pigment epithelium and photoreceptor layers can both be affected. It manifests with signs ...ranging from asymptomatic peripheral salt‐and‐pepper retinopathy to classic bone‐spicule pigmentary changes. The consequences can be progressive mild or severe visual field constriction and central visual acuity loss. The pathophysiological mechanisms involved in retinal dysfunction in mitochondrial disease are still being elucidated and may include a range of metabolic and bioenergetic defects.
Mitochondrial conditions affecting the eye that display prominent outer retinal involvement include.
(a) mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) secondary to the m.3243A > G mtDNA mutation in MT‐TL1,
(b) neuropathy, ataxia and retinitis pigmentosa (NARP) secondary to the m.8993 T > G mtDNA mutation in MT‐ATP6,
(c) chronic progressive external ophthalmoplegia (CPEO), in particular the Kearns‐Sayre syndrome (KSS) secondary to single large‐scale mtDNA deletions, and.
(d) some newer entities, such as optic neuropathy and pigmentary retinopathy seen in patients with mutations in the gene SSBP1.
The features and diagnostic pathway for these conditions will be illustrated and discussed.
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