summary: The kynurenine pathway is not only important for eye pigmentation, but also plays a role in maintaining retinal health.
sauce: Max Planck Institute
Metabolic pathways consist of a series of biochemical reactions within the cell that transform starting components into other products.
There is growing evidence that metabolic pathways coupled with external stressors influence cell and tissue health. Many human diseases, including retinal and neurodegenerative diseases, are associated with imbalances in metabolic pathways.
Elisabeth Knust leads a team of researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, to study the role of one such metabolic pathway in maintaining retinal health under conditions of stress. explained that they play an important role.
They studied the classic Drosophila genes vermilion, cardinal, white and scarlet. These genes were originally characterized decades ago and named for their role in the formation of eye color pigmentation, specifically the brown pigment in fly eyes.
These genes encode components of the kynurenine pathway, whose activity converts the amino acid tryptophan to other products at various steps. In this study, the authors emphasized the function of this metabolic pathway in retinal health, independent of its role in pigmentation.
The kynurenine pathway is an evolutionarily conserved metabolic pathway that regulates a variety of biological processes. Its disruption can lead to the accumulation of toxic or protective biomolecules or metabolites, which can worsen or improve brain health, including the retina, respectively.
Our knowledge of this important metabolic pathway was recently extended in a journal publication by a research team led by Knust, Honorary Director of MPI-CBG. PLOS Genetics.
Recognizing the remarkable conservation of this metabolic pathway and the genes that regulate it, they used the fly as a model system to elucidate the role of individual metabolites in retinal health.
The researchers looked at four genes — cinnabar, cardinal, white and scarlet — named for their unusual eye color after being lost in flies.
“Because the kynurenine pathway is conserved from flies to humans, we investigated whether these genes regulate retinal health independently of their role in pigmentation,” said one of the study’s first authors. One Sarita Hebbar said.
To elucidate this, scientists used a combination of genetics, dietary changes, and biochemical analysis of metabolites to study various mutations in Drosophila.
Co-author Sofia Traikov developed a biochemical assay for metabolites of the kynurenine pathway. This allowed researchers to associate different metabolite levels with retinal health.
They found that one of its metabolites, 3-hydroxykynurenine (3OH-K), damages the retina. More importantly, the degree of denaturation is influenced by the balance between the toxic 3OH-K and protective metabolites such as kynurenic acid (KYNA), suggesting that it is not just their absolute amounts. It is a matter of nature.
“We also gave normal (non-mutated) flies two of these metabolites and found that 3OH-K enhanced stress-induced retinal damage, whereas KYNA reduced stress-related damage,” Sarita said. We found that it protects the retina from This means that altering the ratio of metabolites in the kynurenine pathway can improve retinal health in certain conditions.
Furthermore, by targeting these four genes, and thus four different steps within the pathway, researchers can determine not only the accumulation of 3OH-K itself, but also its location within the cell and thus its availability for further reactions. I was able to demonstrate that the same is true for sex. Important for retinal health.
“This study shows that not only is the kynurenine pathway important in pigmentation, but that levels of individual metabolites play important roles in maintaining retinal health.
“In the future, therapeutic strategies for diseases with kynurenine pathway dysfunction observed in various neurodegenerative conditions should take into account the proportions of different metabolites and their specific sites of accumulation and activity.” I have.”
About this genetics and visual neuroscience research news
author: press office
sauce: Max Planck Institute
contact: Press Office – Max Planck Institute
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Original research: open access.
“Modulation of the kynurenine pathway or sequestration of the toxic 3-hydroxykynurenine protects the retina from light-induced damage in DrosophilaBy Elizabeth Knust et al. PLOS Genetics
overview
Modulation of the kynurenine pathway or sequestration of the toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila
Tissue health is regulated by a myriad of extrinsic and intrinsic factors.
Here, we investigated the role of the conserved kynurenine pathway (KP) in maintaining retinal homeostasis in the context of light stress Drosophila melanogaster. Cinnabar, cardinal and scarlet A fly gene that encodes the various steps of KP.together Whitethese genes are known to be regulators of brown pigment (ommochrome) biosynthesis.
use White As a sensitized genetic background we show that mutation Cinnabar, cardinal and scarlet Differentially modulates light-induced retinal damage.
Mass spectrometry measurements of KP metabolites in flies with different genetic combinations support the notion that increased levels of 3-hydroxykynurenine (3OH-K) and xanthurenic acid (XA) enhance retinal damage. , kynurenic acid (KYNA) and kynurenine (K) are neuronal. -protection.
This conclusion was supported by showing that 3OH-K feeding enhanced retinal damage, whereas KYNA feeding protected the retina in sensitized genetic backgrounds. Interestingly, the detrimental effects of free 3OH-K are reduced by its intracellular compartmentalization.
Sequestering 3OH-K can reduce its toxicity through conversion to a brown pigment or binding to proteins. This work allowed us to separate the role of these KP genes in ommochrome formation from their role in retinal homeostasis.
Furthermore, we propose new hypotheses regarding the importance of the balance of KP metabolites and their compartmentalization in disease mitigation.
