The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway

Banh, Robert S.; Kim, Esther; Spillier, Quentin; Biancur, Douglas E.; Yamamoto, Keisuke; Sohn, Albert S.W.; Shi, Guang; Jones, Drew R.; Kimmelman, Alec C.; Pacold, Michael E.

doi:10.1038/s41586-021-03865-w

Cited by 28 publications

(25 citation statements)

References 40 publications

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“…This result may be related to the melanin deposition and sexual maturation conflict of Wu Liang Shan black-bone chicken. (R)-4-Hydroxymandelate as an intermediated involved in the biosynthesis of the coenzyme Q10 (CoQ10) [ 54 ] and plays a key role in mitochondrial oxidative stress [ 55 ]. Overall, we speculate that oxidative stress may effect the amino acid metabolism of follicles and lead to early or delayed sexual maturation.…”

Section: Discussionmentioning

confidence: 99%

Untargeted Metabolomics Revealed Potential Biomarkers of Small Yellow Follicles of Chickens during Sexual Maturation

et al. 2023

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Sexual maturation provides economically important traits in poultry production. Research on the initiation mechanism of sexual maturity is of great significance for breeding high-yield laying hens. However, the underlying mechanisms are not fully clear. Here, one hundred and fifty Chahua No. 2 laying hens (the CH2 group, which has precocious puberty) and one hundred and fifty Wu Liang Shan black-bone laying hens (the WLS group, a late-maturing chicken breed) with similar weights and ages were randomly selected. ELISA was used to determine the secretion levels of luteinizing hormone (LH), estradiol (E2), and progesterone (P4) in 150-day-old serum and small yellow follicle (SYF) tissues. A histology examination, immunohistochemistry, and quantitative real-time PCR (qPCR) were used to explore the molecular mechanism of how some genes related to oxidative stress affect sexual maturation. The results showed that the secretion levels of LH, E2, and P4 in the CH2 group serum and SYF were higher than those in the WLS group. The results of the real-time PCR of all genes showed that the expression levels of cytochrome P450 family 11 subfamily A member 1, steroidogenic acute regulatory protein, follicle-stimulating hormone receptor, and cytochrome P450 family 19 subfamily A member 1 in the CH2 group were significantly higher than those in the WLS groups (p < 0.001). Untargeted metabolomics combined with multivariate statistical analysis was used to identify biomarkers of SYF tissues in the CH2 and WLS groups. A trajectory analysis of the principal component analysis (PCA) results showed that the samples within the group were clustered and that the samples were dispersed between the CH2 and the WLS groups, indicating that the results of the measured data were reliable and could be used for further research. Further analysis showed that a total of 319 metabolites in small yellow follicles of the CH2 and WLS groups were identified, among which 54 downregulated differential metabolites were identified. These 54 metabolites were found as potential CH2 biomarkers compared with WLS at 150 days, and the different expressions of L-arginine, L-prolinamide, (R)-4-hydroxymandelate, glutathione, and homovanillic acid were more significant. Twenty metabolic pathways were found when significantly differential metabolites were queried in the KEGG database. According to the impact values of the metabolic pathways, eighteen differential metabolites belonged to the mTOR signaling pathway, glutathione metabolism, ABC transporters, the cell ferroptosis pathway, and D-arginine and D-ornithine metabolism. Interestingly, we identified that the cell ferroptosis pathway played an important role in chicken follicle selection for the first time. The histology and immunohistochemistry of SYF showed that the number of granulosa cells increased in the CH2 groups and the expression levels of glutathione peroxidase 4, tumor protein p53, ribosomal protein S6 kinase, and sterol regulatory element binding protein 1 in the granulosa cell layer were upregulated in the CH2 group at the time of sexual maturation. Furthermore, we also speculated that the antioxidant system may play an indispensable role in regulating sexual maturity in chickens. Overall, our findings suggest differentially expressed metabolites and metabolic pathways between CH2 and WLS chickens, providing new insights into the initiation mechanism of sexual maturation.

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Section: Discussionmentioning

confidence: 99%

Untargeted Metabolomics Revealed Potential Biomarkers of Small Yellow Follicles of Chickens during Sexual Maturation

et al. 2023

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“…It is still unknown whether the last step is also conserved in plants. A recent report showed that hydroxyphenylpyruvate dioxygenase-like catalyzes the second reaction in mitochondria of human cells, converting 4-hydroxyphenylpyruvate to 4-hydroxymandelate ( Banh et al., 2021 ). However, Arabidopsis has no homolog of hydroxyphenylpyruvate dioxygenase-like.…”

Section: Aromatic Ring Precursor Biosynthesismentioning

confidence: 99%

How plants synthesize coenzyme Q

Yang

et al. 2022

Plant Communications

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“…Coenzyme Q 10 (CoQ 10 ) is an essential component of the mitochondrial electron transport chain. Primary CoQ 10 deficiencies are rare, clinically and genetically heterogeneous disorders caused by variants in 11 distinct genes encoding proteins of CoQ 10 biosynthesis 1‐3 . COQ4 encodes a ubiquitously expressed protein involved in organizing a multi‐enzyme complex required for CoQ 10 biosynthesis 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Primary CoQ 10 deficiencies are rare, clinically and genetically heterogeneous disorders caused by variants in 11 distinct genes encoding proteins of CoQ 10 biosynthesis. [1][2][3] COQ4 encodes a ubiquitously expressed protein involved in organizing a multi-enzyme complex required for CoQ 10 biosynthesis. 4 Bi-allelic variants in COQ4 have been reported in patients with a neonatal lethal encephalopathy 5,6 infantile mitochondrial multiorgan disorder, 7,8 as well as childhood-onset ataxia, sometimes with stroke-like episodes.…”

Section: Introductionmentioning

confidence: 99%

Bi‐Allelic COQ4 Variants Cause Adult‐Onset Ataxia‐Spasticity Spectrum Disease

et al. 2022

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Background: COQ4 codes for a mitochondrial protein required for coenzyme Q 10 (CoQ 10 ) biosynthesis. Autosomal recessive COQ4associated CoQ 10 deficiency leads to an early-onset mitochondrial multi-organ disorder. Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines.Results: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ 10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. Conclusion:We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported.

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The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway

Cited by 28 publications

References 40 publications

Untargeted Metabolomics Revealed Potential Biomarkers of Small Yellow Follicles of Chickens during Sexual Maturation

Untargeted Metabolomics Revealed Potential Biomarkers of Small Yellow Follicles of Chickens during Sexual Maturation

How plants synthesize coenzyme Q

Bi‐Allelic COQ4 Variants Cause Adult‐Onset Ataxia‐Spasticity Spectrum Disease

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