A transient decrease in mitochondrial activity is required to establish the ganglion cell fate in retina adapted for high acuity vision

Brodier, Laurent; Rodrigues, Tania; Matter-Sadzinski, Lidia; Matter, Jean‐Marc

doi:10.1101/2020.03.23.002998

Cited by 3 publications

(4 citation statements)

References 54 publications

(7 reference statements)

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“…Both Txnip and Txnip.C247S increased the ratio of J-aggregates:JC1-monomers (Figure 5C,D), indicating an increased ΔΨm and/or a greater number/size of mitochondria with a high ΔΨm following Txnip overexpression. This finding was further investigated in vivo using infection by an AAV encoding mitoRFP, which only accumulates in mitochondria with a high ΔΨm (Brodier et al, 2020;Hood et al, 2003). Compared to the control cones without Txnip transduction, the intensity of mitoRFP was higher in P20 rd1 cones transduced with Txnip (Figure 5 -figure supplement 1C,D).…”

Section: Resultsmentioning

confidence: 86%

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Xue

Wang

Rana

et al. 2021

eLife

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Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

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Section: Resultsmentioning

confidence: 86%

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Xue

Wang

Rana

et al. 2021

eLife

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“…5c,d), indicating an increased ΔΨm and/or a greater number/size of mitochondria with a high ΔΨm following Txnip overexpression. This finding was further investigated in vivo using infection by an AAV encoding mitoRFP, which only accumulates in mitochondria with a high ΔΨm (Brodier et al, 2020;Hood et al, 2003). Compared to the control cones without Txnip treatment, the intensity of mitoRFP was higher in P20 rd1 cones treated with Txnip (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 92%

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Xue

Wang

Rana

et al. 2021

Preprint

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Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a gene-agnostic therapy, we screened ≈20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

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“…Retina were transfected with a CMV-GFP reporter together with an ubiquitous mitochondria-targeted label (CMV-mitoDsRed2), whose accumulation in mitochondria has been shown to depend on mitochondrial membrane potential. 20 Results indicated a drop of mitochondrial activity ( Fig. 1D), which in the pigeon was delayed by ∼3 days, suggesting that the temporal pattern of mitochondrial activity, unlike mitochondrial mass, is related to neurogenesis.…”

Section: Mitochondrial Oxidative Metabolism Decreases During Retinal mentioning

confidence: 94%

“…1F). 20 To assess mitochondrial activity in newly differentiated RGCs, confocal, time-lapse imaging, and kymograph analysis of outgrowing axons were performed 24 hours after electroporation of E5 retinas with Chrnb3-GFP, CMV-GFP, and CMV-MitoDsRed2 plasmids. The results shown in Figures 1G through 1J indicate that active mitochondria, located in the RGC axons ( Fig.…”

Section: Mitochondrial Oxidative Metabolism Decreases During Retinal mentioning

confidence: 99%

The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics

Cherix

Brodier

Poitry‐Yamate

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The avian eye is an established model for exploring mechanisms that coordinate morphogenesis and metabolism during embryonic development. Less is known, however, about trafficking of bioenergetic and metabolic signaling molecules that are involved in retinal neurogenesis. METHODS. Here we tested whether the known 3-day delayed neurogenesis occurring in the pigeon compared with the chick was associated with a deferred reshaping of eye metabolism in vivo. Developmental metabolic remodeling was explored using 1 Hmagnetic resonance spectroscopy of the whole eye and vitreous body, in ovo, in parallel with biochemical and molecular analyses of retinal, vitreous, and lens extracts from bird embryos. RESULTS. Cross-species comparisons enabled us to show that a major glycolytic switch in the retina is related to neurogenesis rather than to eye growth. We further show that the temporal emergence of an interlocking regulatory cascade controlling retinal oxidative phosphorylation and glycolysis results in the exchange of lactate and citrate between the retina and vitreous. CONCLUSIONS. Our results point to the vitreous as a reservoir and buffer of energy metabolites that provides trophic support to oxidative neurons, such as retinal ganglion cells, in early development. Through its control of key glycolytic regulatory enzymes, citrate, exchanged between extracellular and intracellular compartments between the retina and vitreous, is a key metabolite in the initiation of a glycolytic switch.

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A transient decrease in mitochondrial activity is required to establish the ganglion cell fate in retina adapted for high acuity vision

Cited by 3 publications

References 54 publications

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics

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