Mitochondrial Dysfunction in the Aging Retina

Eells, Janis T.

doi:10.3390/biology8020031

Cited by 98 publications

(76 citation statements)

References 51 publications

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“…On the other hand, NMNAT3 deficient mice (Nmnat3 KO ) are viable with splenomegaly and hemolytic anemia 44 . Mitochondrial dysfunction is associated with various retinal diseases including diabetic retinopathy, glaucoma and agerelated macular degeneration 45,46 . We generated Nmnat3 KO mice and investigated their retinal function using ERG.…”

Section: Resultsmentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

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Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD + homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration.To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of photoreceptors, indicating these cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the photoreceptor, as conditional deletion of NMNAT1 in photoreceptors but not retinal pigment epithelial cells is sufficient to cause photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving photoreceptor cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway that is active in the setting of dysregulated NAD + metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.

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Section: Resultsmentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

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“…2A ). The macula is under considerable oxidative stress due to its high metabolic rate, high oxygen tension, and the continuous production of reactive oxygen species (ROS) in the area ( Stefánsson et al, 2011 ; Eells, 2019 ; Stefánsson et al, 2019 ). In AMD, pathological changes can be observed in the choriocapillaris, Bruch's membrane, RPE, and photoreceptors ( Fig.…”

Section: Introduction To Rpe Degeneration and Development Of Amdmentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Kaarniranta

Uusitalo

Błasiak

et al. 2020

Progress in Retinal and Eye Research

325

284

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Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

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“…Janis T. Eells [6] reviews the role of mitochondria in one of the body’s most bioenergetic organs, the retina. The eye is exposed to visible light and has extensive antioxidant protective mechanisms.…”

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confidence: 99%