Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure

Fan, Jason; Du, Wen; Kim-Muller, Ja Young; Son, Jaesung; Kuo, Taiyi; Larrea, Delfina; Garcia, Christian; Kitamoto, Takumi; Kraakman, Michael J; Owusu-Ansah, Edward; Cirulli, Vincenzo; Accili, Domenico

doi:10.1016/j.molmet.2019.12.008

Cited by 37 publications

(32 citation statements)

References 68 publications

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“…Our study disclosed the prognostic value of B4GALT2, GOT2, and HMGCS2 in HCC. CYB5R3 functions in drug metabolism, cholesterol biosynthesis, desaturation of fatty acids, and mitochondrial electron transport chain (ETC) activity ( Fan et al, 2020 ). HEXB participates in catalyzing the degradation of the ganglioside GM2 ( Kuil et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Zhao

Zhang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Background: Hepatocellular carcinoma (HCC) is the world’s second most deadly cancer, and metabolic reprogramming is its distinguishing feature. Among metabolite profiling, variation in amino acid metabolism supports tumor proliferation and metastasis to the most extent, yet a systematic study on the role of amino acid metabolism-related genes in HCC is still lacking. An effective amino acid metabolism-related prediction signature is urgently needed to assess the prognosis of HCC patients for individualized treatment.Materials and Methods: RNA-seq data of HCC from the TCGA-LIHC and GSE14520 (GPL3921) datasets were defined as the training set and validation set, respectively. Amino acid metabolic genes were extracted from the Molecular Signature Database. Univariate Cox and LASSO regression analyses were performed to build a predictive risk signature. K-M curves, ROC curves, and univariate and multivariate Cox regression were conducted to evaluate the predictive value of this risk signature. Functional enrichment was analyzed by GSEA and CIBERSORTx software.Results: A nine-gene amino acid metabolism-related risk signature including B3GAT3, B4GALT2, CYB5R3, GNPDA1, GOT2, HEXB, HMGCS2, PLOD2, and SEPHS1 was constructed to predict the overall survival (OS) of HCC patients. Patients were separated into high-risk and low-risk groups based on risk scores and low-risk patients had lower risk scores and longer survival time. Univariate and multivariate Cox regression verified that this signature was an independent risk factor for HCC. ROC curves showed that this risk signature can effectively predict the 1-, 2-, 3- and 5-year survival times of patients with HCC. Additionally, prognostic nomograms were established based on the training set and validation set. These genes were closely correlated with the immune regulation.Conclusion: Our study identified a nine-gene amino acid metabolism-related risk signature and built predictive nomograms for OS in HCC. These findings will help us to personalize the treatment of liver cancer patients.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Zhao

Zhang

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Conversely, mice with a β-cell-specific deletion of CYB5R3 had impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycaemia. Moreover, respiratory response to glucose was blunted in CYB5R3-deficient cells, which also displayed impaired NAD + homeostasis and extensive mitochondrial abnormalities (Fan et al 2020). On the other hand, Tg mice overexpressing CYB5R3 showed less inflammation and decreased oxidative damage, and were protected against induced cancer, which resembled the healthy effect of CR.…”

Section: Introductionmentioning

confidence: 96%

Mitochondrial adaptations in liver and skeletal muscle to pro-longevity nutritional and genetic interventions: the crosstalk between calorie restriction and CYB5R3 overexpression in transgenic mice

et al. 2020

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Calorie restriction without malnutrition (CR) is considered as the most effective nongenetic nor pharmacological intervention that promotes healthy aging phenotypes and can extend lifespan in most model organisms. Lifelong CR leads to an increase of cytochrome b 5 reductase-3 (CYB5R3) expression and activity. Overexpression of CYB5R3 confers some of the salutary effects of CR, although the mechanisms involved might be independent because key aspects of energy metabolism and lipid profiles of tissues go in opposite ways. It is thus important to study if some of the metabolic adaptations induced by CR are affected by CYB5R3 overexpression. CYB5R3 overexpression greatly preserved body and liver weight in mice under CR conditions. In liver, CR did not modify mitochondrial abundance, but lead to increased expression of mitofusin Mfn2 and TFAM, a transcription factor involved in mitochondrial biogenesis. These changes were prevented by CYB5R3 overexpression but resulted in a decreased expression of a different mitochondrial biogenesis-related transcription factor, Nrf1. In skeletal muscle, CR strongly increased mitochondrial mass, mitofusin Mfn1, and Nrf1. However, CYB5R3 mice on CR did not show increase in muscle mitochondrial mass, regardless of a clear increase in expression of TFAM and mitochondrial complexes in this tissue. Our results support that CYB5R3 overexpression significantly modifies the metabolic adaptations of mice to CR.

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“…In IKO β-cells, we detected the expected alterations of known FoxO1 target mRNAs, with increased glycolytic genes [ 39 ], including β-cell “disallowed” genes [ 7 ] and Aldh1a3 [ 36 ], as well as decreased Cyb5r3 [ 40 ] ( Table S1 ). These data were consistent with previous findings indicating that triple FoxO ablation results in altered metabolic coupling [ 3 ].…”

Section: Resultsmentioning

confidence: 99%

“…In our cross, the most striking gene expression changes in HKO were the substantial increases in abundant mRNAs encoding mitochondrial cytochrome components (COX, CYTB, ND1, ND2, ND4, and ND5) ( Table S2 ). Conversely, the mitochondrial complex III oxidoreductase Cyb5r3 was decreased, possibly resulting in altered electron transport across the mitochondrial chain [ 40 ]. There were extensive increases in the family of KCN-type potassium channels, which may have affected membrane depolarization and insulin secretion, thus explaining the preserved response to sulfonylurea ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the absent sulfonylurea response in FoxO1 knockout mice was reminiscent of the acquired failure seen in diabetic patients, while Hnf4α knockout showed a preserved sulfonylurea response similar to MODY1 patients [ 11 ]. The extent to which the recently characterized Foxo1 target Cyb5r3 was responsible for some of the impairment of insulin secretion seen herein is currently under investigation by our laboratory [ 40 ]. The calcium response to glucose differed in the FoxO1 and Hnf4α single mutants, although this may partly be explained by the compensatory function of FoxO3 in single FoxO1 knockouts [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

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Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function

Kuo

Miyachi

et al. 2021

Molecular Metabolism

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Objective Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components and act through β-cell-specific enhancers. However, their relationship is unclear. Methods In this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells enriches active Hnf4α enhancers according to a HOMER analysis. Results To model the functional significance of this predicted unusual enhancer utilization, we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea and calcium fluxes. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues was completely reversed in double mutants lacking FoxO1 and Hnf4α. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of β-cell dysfunction. An antagonistic network regulating glycolysis, including β-cell “disallowed” genes, and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. Conclusions The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.

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Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure

Cited by 37 publications

References 68 publications

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Mitochondrial adaptations in liver and skeletal muscle to pro-longevity nutritional and genetic interventions: the crosstalk between calorie restriction and CYB5R3 overexpression in transgenic mice

Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function

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