Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury

Moos, Walter H.; Faller, Douglas V.; Glavas, Ioannis P.; Harpp, David N.; Kamperi, Natalia; Kanara, Iphigenia; Kodukula, Krishna; Mavrakis, Anastasios; Pernokas, Julie; Pernokas, Mark; Pinkert, Carl A.; Powers, Whitney R.; Sampani, Konstantina; Steliou, Kosta; Tamvakopoulos, Constantin; Vavvas, Demetrios G.; Zamboni, Robert; Chen, Xiaohong

doi:10.1016/j.bcp.2022.115168

Cited by 18 publications

(21 citation statements)

References 287 publications

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“…More than 60% of retinal mitochondria are in photoreceptor cells 23 . When mitochondrial dysfunction occurs, it may lead to the death of photoreceptor cells 24 , and denaturation of neurons 25 . After retinal detachment, the up-regulation of L-palmitoylcarnitine level caused by hypoxia in the inner retina may aggravate the damage of visual function.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics in vitreous fluid of retinal detachment associated with choroidal detachment patients

Yang

Luo

Chen

et al. 2023

Preprint

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Background Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a complex type of retinal detachment. This disease is characterized by high difficulty of operation and poor prognosis. However, the pathogenesis is still unclear. The purpose of this study was to analyze the changes of metabolites and metabolic pathways in vitreous fluid of RRDCD patients. Method Using ultra-high-performance liquid chromatography coupled with the quadrupole time-of-flight mass spectrometry method, metabolites in the vitreous fluid of RRDCD and idiopathic epimacular membrane (IEMM) patients were analyzed. A total of 28 samples were analyzed to compare the significance of different metabolites between these groups. Results We identified 135 different metabolites between the RRDCD and IEMM groups (VIP > 1, P value < 0.05). Compared with the IEMM group, the level of sphingomyelin, adenosine, L-palmitoylcarnitine and 4,7,10,13,1 6,19-docosahexaenoic acid up-regulated in RRDCD group. A series of lipid metabolites were up-regulated in RRDCD group. The main metabolic pathways involved were protein digestion and absorption, ABC transporters, aminoacyl-tRNA biosynthesis, central carbon metabolism in cancer and sphingolipids metabolism. Conclusions Our results suggest that the up-regulation of sphingomyelin and abnormal sphingolipids metabolism may induce cell migration and death after retinal or choroidal detachment. And then, it may induce intraocular inflammation and damage visual function. The accumulated L-palmitoylcarnitine and fatty acid metabolites may damage the energy pathway of retina, and aggravate the death of photoreceptors after hypoxia. These results provide clues for studying the mechanism, treatment and prognosis of RRDCD.

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Section: Discussionmentioning

confidence: 99%

Metabolomics in vitreous fluid of retinal detachment associated with choroidal detachment patients

Yang

Luo

Chen

et al. 2023

Preprint

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“…In AMD both the RPE and photoreceptors have been shown to display mitochondrial complex 1 deficiency [ 16 , 26 , 46 , 47 , 48 , 49 , 50 , 51 ]. Complex 1, a component of the mitochondrial electron transport chain (ETC), is a 45-subunit complex, 7 of which are mitochondrially encoded [ 51 ].…”

Section: Introductionmentioning

confidence: 99%

RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models

Millington‐Ward

Chadderton

Finnegan

et al. 2023

IJMS

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Age-related macular degeneration (AMD) is the most common cause of blindness in the aged population. However, to date there is no effective treatment for the dry form of the disease, representing 85–90% of cases. AMD is an immensely complex disease which affects, amongst others, both retinal pigment epithelium (RPE) and photoreceptor cells and leads to the progressive loss of central vision. Mitochondrial dysfunction in both RPE and photoreceptor cells is emerging as a key player in the disease. There are indications that during disease progression, the RPE is first impaired and RPE dysfunction in turn leads to subsequent photoreceptor cell degeneration; however, the exact sequence of events has not as yet been fully determined. We recently showed that AAV delivery of an optimised NADH-ubiquinone oxidoreductase (NDI1) gene, a nuclear-encoded complex 1 equivalent from S. cerevisiae, expressed from a general promoter, provided robust benefit in a variety of murine and cellular models of dry AMD; this was the first study employing a gene therapy to directly boost mitochondrial function, providing functional benefit in vivo. However, use of a restricted RPE-specific promoter to drive expression of the gene therapy enables exploration of the optimal target retinal cell type for dry AMD therapies. Furthermore, such restricted transgene expression could reduce potential off-target effects, possibly improving the safety profile of the therapy. Therefore, in the current study, we interrogate whether expression of the gene therapy from the RPE-specific promoter, Vitelliform macular dystrophy 2 (VMD2), might be sufficient to rescue dry AMD models.

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“…The tricarboxylic acid (TCA) cycle promotes cell death and produces a proteotoxic stimulus [7]. The recent ndings have demonstrated that cuproptosis is highly correlated with a variety of diseases, as well as cancer [8][9][10]. For this reason, it is signi cant to identify cancer related biomarkers that can be used to facilitate improvement in patient progression and outcome prediction.…”

Section: Introductionmentioning

confidence: 99%

Identification of A Novel Cuproptosis-related lncRNAs for the Prognostic and Immune Landscape in Wilms Tumor

Xie

Wang

et al. 2023

Preprint

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Background In contrast to all other known kinds of regulated cell death, cuproptosis is a unique copper-dependent cell death pathway that has a close connection to mitochondria and metabolism. The pathogenesis of Wilms tumor (WT), a common pediatric abdominal tumor, has yet to be fully defined. Besides, previous studies on lncRNAs related to Cuproptosis in WT and the connection between Wilms tumor, the microenvironment, and cuproptosis are still scarce.Results Our results show that Individuals with WT and high-risk group identified utilizing the signature were related to poorer survival outcomes. The study revealed that high-risk group had a worse prognosis (P < 0.001) in contrast with the group of low-risk. The risk score AUC for this signature was 0.818, which was higher than the risk score for age (0.524), sex (0.580), race (0.489), stage (0.673) and the modeling of ferroptosis-related lncRNAs (0.775). Individuals in the group of low-risk had an elevated TIDE scores ratio and were more sensitive to 13 drugs, including BI-2536, EX-527, IspinesibMesylate, KIN001-135, etc.Conclusions Our model can precisely predict the WT patients' prognosis and differentiate between low- and high-risk WT patients. It is hoped that this study will give a novel method for clinical prognosis and appropriate WT patients therapy.

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Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury

Cited by 18 publications

References 287 publications

Metabolomics in vitreous fluid of retinal detachment associated with choroidal detachment patients

Metabolomics in vitreous fluid of retinal detachment associated with choroidal detachment patients

RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models

Identification of A Novel Cuproptosis-related lncRNAs for the Prognostic and Immune Landscape in Wilms Tumor

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