The one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters

Schober, F.; Moore, David; Atanassov, Ilian; Moedas, Marco F.; Clemente, Paula; Végvári, Ákos; Fissi, Najla El; Filograna, Roberta; Bucher, Anna-Lena; Hinze, Yvonne; Hedman, Erik; Chernogubova, Ekaterina; Begzati, Arjana; Wibom, Rolf; Jain, Mohit; Nilsson, Roland; Käll, Lukas; Wedell, Anna; Freyer, Christoph; Wredenberg, Anna

doi:10.1126/sciadv.abf0717

Cited by 31 publications

(41 citation statements)

References 75 publications

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“…Zhang et al have been able to elegantly demonstrate that, in addition to the SARS-CoV-2 hijacking of one-carbon metabolism, it also hijacks folate (folic acid), and that folate metabolism is absolutely critical for the transfer of one-caron units for nucleotide synthesis in addition to its important role in glutathione synthesis via the transsulfuration pathway [69]. In addition, Schober et al have demonstrated that the one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters [70].…”

Section: Compromised Folate-mediated One-carbon Metabolism (Focm) In Lc/pasc: Importance Of Hyperhomocysteinemia (Hhcy) and Deficient Micmentioning

confidence: 99%

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

Hayden

2021

Neuroglia

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The COVID-19 pandemic has paralleled the great Spanish flu pandemic of 1918–1919 in the United States. Previous historical accounts have strongly suggested a post-viral syndrome and, currently, a post-COVID-19 viral syndrome is unquestionable, which shares many of the characteristics of myalgic encephalomyelitis/chronic fatigue syndrome that is present globally. The original term for this post-acute sequela of SARS-CoV-2 (PASC) was termed long haulers by those who were affected with this syndrome and it is now termed long COVID (LC) or PASC. International researchers and clinicians are desperately trying to better understand the pathobiological mechanisms possibly involved in this syndrome. This review aims to summarize many of the cumulated findings associated with LC/PASC and provides supportive and representative illustrations and transmission electron micrographic remodeling changes within brain tissues associated with a stress type of injury as occurs in the classic db/db and novel BTBR ob/ob obesity and diabetes mellitus mice models. These models are utilized to merely provide a response to metabolic stress injury wound healing mechanisms that are also present in humans. This review posits that neuroglial activation and chronic neuroinflammation may be a common denominator for the development of the complex LC/PASC syndrome following acute COVID-19 due to SARS-CoV-2.

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Section: Compromised Folate-mediated One-carbon Metabolism (Focm) In Lc/pasc: Importance Of Hyperhomocysteinemia (Hhcy) and Deficient Micmentioning

confidence: 99%

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

Hayden

2021

Neuroglia

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“…More detailed STRING network analysis identified that previously established nucleotide metabolism was affected, as well as glutathione and Fe-S signalling, all of which are tightly linked to mitochondrial function. A recent study has reported that mitochondrial S-adenosylmethionine (SAM) (mitoSAM) production depends on one-carbon metabolism, and that mitoSAM depletion leads to dysregulation of ISC biosynthesis, linking nucleotide metabolism and ISC synthesis with mitochondrial function [ 63 ]. Glutathione metabolism is also related to the methionine cycle, as its product homocysteine can lead to glutathione production via the trans-sulphuration pathway.…”

Section: Discussionmentioning

confidence: 99%

Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

Popovic

Celardo

et al. 2021

IJMS

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In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.

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“…Although the influence of SAM plays a key role in the regulation of DNA methylation, it is difficult to conclude that changes in the content of SAM can be used as all factors for changes in the degree of methylation. Schober et al [ 32 ] reported that the one-carbon metabolite and methyl group donor SAM is pivotal for energy metabolism. This further illustrates that the mechanism by which SAM affects DNA methylation changes is complex and diverse.…”

Section: Discussionmentioning

confidence: 99%

Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish

Han

Wang

Jin

et al. 2021

Biology

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Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. Moreover, we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid and mthfr−/− mutant all gave rise to early pericardial edema and cardiac defect at 3 days post fertilization (dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5 dpf. The expression levels of cardiac marker genes hand2, gata4, and nppa changed in the abnormality of folate metabolism embryos and mthfr−/− mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. Furthermore, our results reveal that folic acid has a dose-dependent effect on early cardiac development. Precise dosage of folic acid supplementation is crucial for the embryonic development of organisms.

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The one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters

Cited by 31 publications

References 75 publications

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

Hypothesis: Neuroglia Activation Due to Increased Peripheral and CNS Proinflammatory Cytokines/Chemokines with Neuroinflammation May Result in Long COVID

Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish

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