MDH1 deficiency is a metabolic disorder of the malate–aspartate shuttle associated with early onset severe encephalopathy

Broeks, Melissa H.; Shamseldin, Hanan E.; Alhashem, Amal; Hashem, Mais; Abdulwahab, Firdous; Alshedi, Tarfa; Alobaid, Iman; Zwartkruis, Fried; Westland, Denise; Fuchs, Sabine A.; Verhoeven‐Duif, Nanda M.; Jans, Judith; Alkuraya, Fowzan S.

doi:10.1007/s00439-019-02063-z

Cited by 40 publications

(47 citation statements)

References 39 publications

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“…MDH1, an NAD(H)dependent enzyme, is an important part in the malate/aspartate shuttle (MAS). 32 This metabolic cycle contributes to maintain intracellular NAD(H) redox homeostasis as it transfers reducing equivalent NAD(H) across the mitochondrial membrane. 32 It has been reported that abnormal expression of MDH1 was related to the tumor occurrence and progression.…”

Section: Discussionmentioning

confidence: 99%

“…32 This metabolic cycle contributes to maintain intracellular NAD(H) redox homeostasis as it transfers reducing equivalent NAD(H) across the mitochondrial membrane. 32 It has been reported that abnormal expression of MDH1 was related to the tumor occurrence and progression. 33 For example, MDH1 promoted pancreatic ductal adenocarcinoma cell proliferation and metabolism through NAD production to support glycolysis.…”

Section: Discussionmentioning

confidence: 99%

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A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

Huang

Zhang

Gong

et al. 2020

Preprint

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Background: Lung cancer is one of the most lethal and most prevalent malignant tumors worldwide, and lung squamous cell carcinoma (LUSC) is one of major histological subtypes. Although, numerous biomarkers were found to be associated with prognosis in LUSC, the prediction effect of a single gene biomarker is not sufficient, especially for glycolysis-related genes. Therefore, we aimed to develop a novel glycolysis-related gene signature to predict survival of patients with LUSC.Methods: The mRNA expression files and clinical information of LUSC were obtained from The Cancer Genome Atlas (TCGA) dataset.Results: Based on Gene set enrichment analysis (GSEA), we found 5 glycolysis-related gene sets were significantly enriched in LUSC tissues. Univariate and multivariate Cox proportional regression models were conducted to choose prognostic-related gene signature. Based on Cox proportional regression model, a risk score of three-gene signature (including HKDC1, ALDH7A1, and MDH1) was established to divide patients into high-risk and low-risk subgroups. We found that a risk score of three-gene signature was an independent of prognostic indicator in LUSC using multivariate Cox regression analysis. Additionally, based on the cBioPortal database, the rate of alterations in HKDC1, ALDH7A1, and MDH1 genes were 1.9%, 1.1%, and 5% in LUSC patients, respectively. Conclusion: In conclusion, a glycolysis-based three-gene signature could serve as a novel biomarker in predicting prognosis of patients with LUSC, which provided more gene targets to cure LUSC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

Huang

Zhang

Gong

et al. 2020

Preprint

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“…MDH1 generates NAD+ upon the reduction of oxaloacetate to malate. MAS is important for intracellular NAD(H) redox homeostasis as it transfers, reducing equivalents across the mitochondrial membrane [63].…”

Section: Key Metabolic Pathways After Single and Integrated Analysismentioning

confidence: 99%

Diet induced the change of mtDNA copy number and metabolism in Angus cattle

Bai

Carrillo

et al. 2020

J Animal Sci Biotechnol

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Background: Grass-fed and grain-fed Angus cattle differ in the diet regimes. However, the intricate mechanisms of different beef quality and other phenotypes induced by diet differences are still unclear. Diet affects mitochondrial function and dynamic behavior in response to changes in energy demand and supply. In this study, we examined the mtDNA copy number, mitochondria-related genes expression, and metabolic biomarkers in grass-fed and grainfed Angus cattle. Results: We found that the grass-fed group had a higher mtDNA copy number than the grain-fed group. Among different tissues, the mtDNA copy number was the highest in the liver than muscle, rumen, and spleen. Based on the transcriptome of the four tissues, a lower expression of mtDNA-encoded genes in the grass-fed group compared to the grain-fed group was discovered. For the mitochondria-related nuclear genes, however, most of them were significantly down-regulated in the muscle of the grass-fed group and up-regulated in the other three tissues. In which, COX6A2, POLG2, PPIF, DCN, and NDUFA12, involving in ATP synthesis, mitochondrial replication, transcription, and maintenance, might contribute to the alterations of mtDNA copy number and gene expression. Meanwhile, 40 and 23 metabolic biomarkers were identified in the blood and muscle of the grain-fed group compared to a grass-fed group, respectively. Integrated analysis of the altered metabolites and gene expression revealed the high expression level of MDH1 in the grain-fed group might contribute to the mitochondrial NADH oxidation and spermidine metabolism for adapting the deletion mtDNA copy number. Conclusions: Overall, the study may provide further deep insight into the adaptive and regulatory modulations of the mitochondrial function in response to different feeding systems in Angus cattle.

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“…Hence these three genes are considered significant biomarkers of COVID-19. Higher levels of Malate Dehydrogenase 1 (MDH1) was associated with schizophrenia (Ritsner, 2011), prions disease (Zerr et al, 2019) and early onset of encephalopathy (Broeks et al, 2019). Elevation of SGCE Sarcoglycan-epsilon gene was attributed to muscular dystrophy (Emery, 2001).…”

Section: Discussionmentioning

confidence: 99%

Computational gene expression profiling in the exploration of biomarkers, non-coding functional RNAs and drug perturbagens for COVID-19

Aishwarya

Gunasekaran

Margret³

2020

Journal of Biomolecular Structure and Dynamics

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The coronavirus disease, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global health crisis that is being endured with an increased alarm of transmission each day. Though the pandemic has activated innumerable research attention to decipher an antidote, fundamental understanding of the molecular mechanisms is necessary to halt the disease progression. The study focused on comparison of the COVID-19 infected lung tissue gene expression datasets-GSE155241 and GSE150316 with the GEO2R-limma package. The significant up-and downregulated genes were annotated. Further evaluation of the enriched pathways, transcription factors, kinases, noncoding RNAs and drug perturbations revealed the significant molecular mechanisms of the host response. The results revealed a surge in mitochondrial respiration, cytokines, neurodegenerative mechanisms and deprived oxygen, iron, copper, and glucose transport. Hijack of ubiquitination by SARS-CoV-2, hox gene differentiation, histone modification, and miRNA biogenesis were the notable molecular mechanisms inferred. Long non-coding RNAs such as C058791.1, TTTY15 and TPTEP1 were predicted to be efficient in regulating the disease mechanisms. Drugs-F-1566-0341, Digoxin, Proscillaridin and Linifanib that reverse the gene expression signatures were predicted from drug perturbations analysis. The binding efficiency and interaction of proscillaridin and digoxin as obtained from the molecular docking studies confirmed their therapeutic potential. Two overlapping upregulated genes MDH1, SGCE and one downregulated gene PFKFB3 were appraised as potential biomarkers candidates. The upregulation of PGM5, ISLR and ANK2 as measured from their expressions in normal lungs affirmed their possible prognostic biomarker competence. The study explored significant insights for better diagnosis, and therapeutic options for COVID-19.

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MDH1 deficiency is a metabolic disorder of the malate–aspartate shuttle associated with early onset severe encephalopathy

Cited by 40 publications

References 39 publications

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

Diet induced the change of mtDNA copy number and metabolism in Angus cattle

Computational gene expression profiling in the exploration of biomarkers, non-coding functional RNAs and drug perturbagens for COVID-19

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