The Antioxidative Function of Alpha-Ketoglutarate and Its Applications

Liu, Shaojuan; He, Liuqin; Yao, Kang

doi:10.1155/2018/3408467

Cited by 89 publications

(110 citation statements)

References 43 publications

(40 reference statements)

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“…Weiss, et al had previously used broad-spectrum metabolomics to report links between altered levels of thymidine and other pyrimidine nucleotide metabolic products and RP in a different RP murine model [55]. Overall, our work, in conjunction with other previously published efforts, suggests that pyrimidine metabolism is altered in RP and may be related to mitochondrial DNA replication pathways [53,54].…”

Section: Metabolite/lipid Imaging Of Retinal Tissue Sections -To Invesupporting

confidence: 64%

“…The most effective therapy tested was ɑ-KG, a key component of the TCA cycle that acts on various downstream metabolic pathways within the cell and determines the overall rate of the energetic process [55] as well as enhancing reductive carboxylation and supporting redox homeostasis in photoreceptors [63,64]. In addition to its metabolic roles, ɑ-KG can be converted to glutamine, and subsequently glutathione GSH, thereby facilitating the synthesis of potent antioxidants in the cell [53]. These antioxidant properties may have beneficial effects in the context of RP therapy.…”

Section: Discussionmentioning

confidence: 99%

“…9D). Therefore, DESI-MSI provided some indication that supplemental ɑ-KG was being consumed to increase levels of TCA metabolites such as aconitic acid and glutamine levels, which likely play a role in the cell's antioxidant response [53].…”

Section: Metabolite/lipid Imaging Of Retinal Tissue Sections -To Invementioning

confidence: 99%

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Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Wert

Vélez

Vijayalakshmi

et al. 2019

Preprint

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One Sentence Summary: The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina. Abstract: 244Main Text: 9,039References: 83 AbstractNeurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death.Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

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Section: Metabolite/lipid Imaging Of Retinal Tissue Sections -To Invesupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Wert

Vélez

Vijayalakshmi

et al. 2019

Preprint

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“…This is done through downregulation of the mitochondrial enzyme AKGDH, reported to be severely diminished in human pathologies where oxidative stress is thought to play a vital role 21 . αKG together with cysteine and glycine, a is involved in GSH synthesis 39,40 . GSH is one of the major cellular antioxidants, protecting cells against ROS.…”

Section: Discussionmentioning

confidence: 99%

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Jamalpoor

Gelder

Yengej

et al. 2020

Preprint

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Nephropathic cystinosis is a severe monogenetic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established proximal tubulopathy. Here, we developed a new therapeutic strategy by applying an omics-based strategy to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a key metabolite linking cystinosin loss, lysosomal autophagy defect and proximal tubular impairment in cystinosis. This insight offered a bicalutamide-cysteamine combination treatment as a novel dual target pharmacological approach for the phenotypical correction of cystinotic proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.

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“…In addition to higher levels of the metabolites described above, we found lower levels of alpha‐ketoglutaric acid and metabolites associated with cellular metabolism in individuals with FM. Alpha‐ketoglutarate is a crucial intermediate of the Krebs cycle and plays a critical role in multiple metabolic processes and acts as an antioxidant agent …”

Section: Discussionmentioning

confidence: 99%

Metabolomic Differentials in Women With and Without Fibromyalgia

Menzies

Starkweather

Yao

et al. 2019

Clinical Translational Sci

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A nontargeted plasma metabolomic analysis was conducted to compare differentially expressed metabolites in women with and without fibromyalgia (FM) using data and samples collected from two parent studies in women with FM (n = 20) and comparative data collected from newly recruited age‐matched women (n = 20). Blood plasma samples were analyzed for metabolite content using liquid chromatography mass spectrometry. Consolidation of positive and negative ion mode metabolomics data with fold change (>2 or <0.5) and variable importance of projection scores ≥1 revealed statistically significant metabolites comparing samples from women with and without FM. Metabolite profiles in patients with FM differed from the comparison group in energy, lipid and amino acid metabolites reflecting heightened oxidative stress, inflammation, and tryptophan degradation in patients with FM. Study results may contribute to further identification of unique metabolomic profiles enhancing understanding of the pathophysiology of FM and for the development of effective therapeutic options.

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The Antioxidative Function of Alpha-Ketoglutarate and Its Applications

Cited by 89 publications

References 43 publications

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Metabolomic Differentials in Women With and Without Fibromyalgia

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