Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens

Jiménez‐Loygorri, Juan Ignacio; Benítez-Fernández, Rocío; Viedma-Poyatos, Álvaro; Zapata‐Muñoz, Juan; Villarejo‐Zori, Beatriz; Gómez‐Sintes, Raquel; Boya, Patricia

doi:10.1016/j.preteyeres.2023.101205

Cited by 20 publications

(8 citation statements)

References 260 publications

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“…1B), both phenotypes present in AMD patients [ 20 ]. The RPE provides trophic support to photoreceptors within the neuroretina, and is essential to ensure their survival [ 21 ]. Supporting our findings, we also detected that UA reduced 4-hydroxynonenal (4-HNE; lipid peroxidation byproduct) levels (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

Jiménez-Loygorri,

Viedma-Poyatos,

Gómez-Sintes

et al. 2024

Mol Neurodegeneration

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Background Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. Methods A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. Results UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. Conclusions Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

Jiménez-Loygorri,

Viedma-Poyatos,

Gómez-Sintes

et al. 2024

Mol Neurodegeneration

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“…Hence, our findings of activating sAC-mediated inhibition of AMPK activation in stressed RGCs suggest that sAC-regulated AMPK activity contributes to mitochondrial protection in RGCs. Mitophagy or autophagy plays a crucial role in mitochondrial qualify control 54 and enhanced mitophagosome formation could be protective in RGCs damaged by glaucomatous insults 42,55 . Indeed, oxidative stress is associated with the reduction of mitophagy by decreasing p62 in glaucomatous retinal degeneration 56 .…”

Section: Discussionmentioning

confidence: 99%

Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress

Bastola,

Perkins,

Huu

et al. 2024

Preprint

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Oxidative stress is a key factor causing mitochondrial dysfunction and retinal ganglion cell (RGC) death in glaucomatous neurodegeneration. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway is involved in mitochondrial protection, promoting RGC survival. Soluble adenylyl cyclase (sAC) is one of the key regulators of the cAMP/PKA signaling pathway. However, the precise molecular mechanisms underlying the sAC-mediated signaling pathway and mitochondrial protection in RGCs that counter oxidative stress are not well characterized. Here, we demonstrate that sAC plays a critical role in protecting RGC mitochondria from oxidative stress. Using mouse models of oxidative stress, we found that activating sAC protected RGCs, blocked AMP-activated protein kinase activation, inhibited glial activation, and improved visual function. Moreover, we found that this is the result of preserving mitochondrial dynamics (fusion and fission), promoting mitochondrial bioenergetics and biogenesis, and preventing metabolic stress and apoptotic cell death in a paraquat oxidative stress model. Notably, sAC activation ameliorated mitochondrial dysfunction in RGCs by enhancing mitochondrial biogenesis, preserving mitochondrial structure, and increasing ATP production in oxidatively stressed RGCs. These findings suggest that activating sAC enhances the mitochondrial structure and function in RGCs to counter oxidative stress, consequently promoting RGC protection. We propose that modulation of the sAC-mediated signaling pathway has therapeutic potential acting on RGC mitochondria for treating glaucoma and other retinal diseases.

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“…Additionally, BNIP3 inhibits the Ras homolog enriched in the brain (Rheb)/mTOR pathway and initiates autophagy (Figure 4) (Lin et al, 2014). Recent studies demonstrated that RPE in AMD has reduced levels of PINK1 and Parkin, and BNIP3/NIX-mediated mitophagy is the key factor in preserving mitochondrial equilibrium (Fisher et al, 2022;Jiménez-Loygorri et al, 2023). Esteban-Martínez and Boya (2018) reported that in response to metabolic stress, the destabilization of HIF1A/ HIF-1 led to the upregulation of mitophagy receptor BNIP3/NIX.…”

Section: Mitophagy Mediated By Bnip3/nixmentioning

confidence: 99%

Potential application of traditional Chinese medicine in age-related macular degeneration—focusing on mitophagy

Yu,

Wang,

Liu

et al. 2024

Front. Pharmacol.

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Retinal pigment epithelial cell and neuroretinal damage in age-related macular degeneration (AMD) can lead to serious visual impairments and blindness. Studies have shown that mitophagy, a highly specialized cellular degradation system, is implicated in the pathogenesis of AMD. Mitophagy selectively eliminates impaired or non-functioning mitochondria via several pathways, such as the phosphatase and tensin homolog-induced kinase 1/Parkin, BCL2-interacting protein 3 and NIP3-like protein X, FUN14 domain-containing 1, and AMP-activated protein kinase pathways. This has a major impact on the maintenance of mitochondrial homeostasis. Therefore, the regulation of mitophagy could be a promising therapeutic strategy for AMD. Traditional Chinese medicine (TCM) uses natural products that could potentially prevent and treat various diseases, such as AMD. This review aims to summarize recent findings on mitophagy regulation pathways and the latest progress in AMD treatment targeting mitophagy, emphasizing methods involving TCM.

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Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens

Cited by 20 publications

References 260 publications

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

Activating soluble adenylyl cyclase protects mitochondria, rescues retinal ganglion cells, and ameliorates visual dysfunction caused by oxidative stress

Potential application of traditional Chinese medicine in age-related macular degeneration—focusing on mitophagy

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