Can folic acid have a role in mitochondrial disorders?

Ormazábal, Aída; Casado, Mercedes; Molero-Luís, Marta; Montoya, Julio; Rahman, Shamima; Aylett, Sophie-Beth; Hargreaves, Iain P.; Heales, Simon; Artuch, Rafael

doi:10.1016/j.drudis.2015.07.002

Cited by 42 publications

(23 citation statements)

References 45 publications

(71 reference statements)

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“…This research naturally leads to the idea that supplementation with formate might benefit patients with Sengers syndrome, or other mitochondrial diseases with perturbations to 1C metabolism. While folate deficiency has been discussed in the context of mitochondrial disease (Garcia-Cazorla et al, 2008;Ormazabal et al, 2015), the underlying mechanisms are poorly understood. One-carbon metabolism is known to play a crucial role in development (Momb et al, 2013), but its function in adult tissues is not clear (Ducker and Rabinowitz, 2017).…”

Section: Discussionmentioning

confidence: 99%

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

Jackson

Hock

Palmer

et al. 2020

Preprint

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words)The Acylglycerol Kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex at the inner mitochondrial membrane. Mutations inAGK cause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. We undertook proteomic profiling of Sengers patient fibroblasts and an AGKKO cell line to map the proteomic changes that ensue upon AGK dysfunction. This uncovered extensive remodelling of mitochondrial one-carbon metabolism enzymes and showed that inner membrane serine transporters, Sideroflexins (SFXNs), are novel substrates of the TIM22 complex. Deletion of SFXN1 recapitulates the remodelling of onecarbon metabolism observed in Sengers patient cells. Proliferation of cells lacking AGK is perturbed in the absence of exogenous serine and rescuable through addition of formate, highlighting the dysregulation of one carbon metabolism as a key molecular feature in the biology of Sengers syndrome.

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Section: Discussionmentioning

confidence: 99%

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

Jackson

Hock

Palmer

et al. 2020

Preprint

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“…This way three metabolic pathways within two interaction modules were identified. Our approach had not only validated previously known aspects of ASD pathogenesis [Frye, Sequeira, et al, ; Frye et al, ; Ormazabal et al, ], but also identified within the third pathway (ref. module 2) a previously uncharacterized relationship between cerebral folate metabolism and the production of IMP.…”

Section: Discussionmentioning

confidence: 87%

“…Folate deficiency could slow down the synthesis of carnitine in mitochondria and thereby disrupt the processes of betaoxidation leading to lack of energy, especially under stress conditions and during fasting. The resulting temporary disruption of ATP synthesis might have multifactorial effects on neurodevelopment and it might also exacerbate the lack of folate in the CNS since its transport across the blood-brain barrier is ATP-dependent [Ormazabal et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

Identification of likely associations between cerebral folate deficiency and complex genetic‐ and metabolic pathogenesis of autism spectrum disorders by utilization of a pilot interaction modeling approach

et al. 2017

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Recently, cerebral folate deficiency (CFD) was suggested to be involved in the pathogenesis of autism spectrum disorders (ASD). However, the exact role of folate metabolism in the pathogenesis of ASD, identification of underlying pathogenic mechanisms and impaired metabolic pathways remain unexplained. The aim of our study was to develop and test a novel, unbiased, bioinformatics approach in order to identify links between ASD and disturbed cerebral metabolism by focusing on abnormal folate metabolism, which could foster patient stratification and novel therapeutic interventions. An unbiased, automatable, computational workflow interaction model was developed using available data from public databases. The interaction network model of ASD-associated genes with known cerebral expression and function (SFARI) and metabolic networks (MetScape), including connections to known metabolic substrates, metabolites and cofactors involving folates, was established. Intersection of bioinformatically created networks resulted in a limited amount of interaction modules pointing to common disturbed metabolic pathways, linking ASD to CFD. Two independent interaction modules (comprising three pathways) covering enzymes encoded by ASD-related genes and folate cofactors utilizing enzymes were generated. Module 1 suggested possible interference of CFD with serine and lysine metabolism, while module 2 identified correlations with purine metabolism and inosine monophosphate production. Since our approach was primarily conceived as a proof of principle, further amendments of the presented initial model are necessary to obtain additional actionable outcomes. Our modelling strategy identified not only previously known interactions supported by evidence-based analyses, but also novel plausible interactions, which could be validated in subsequent functional and/or clinical studies. Autism Res 2017, 10: 1424-1435. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

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“…Accumulation of somatic deletions and mutations in the mtDNA may play a role in tumorigenesis, as mtDNA is subjected to detrimental factors originating from the environment, including dietary deficits [73]. Damage to mtDNA is capable of inducing reactions that can damage the nuclear DNA as well, by both genetic and epigenetic mechanisms, including methylation, chromatin remodelling and signalling pathways [74].…”

Section: Folate Deficiency and Genomic Damagementioning

confidence: 99%

Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature

et al. 2017

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BackgroundFolic acid and its derivates, known as folates, are chemoprotective micronutrients of great interest because of their essential role in the maintenance of health and genomic integrity. The supplementation of folic acid during pregnancy has long been known to reduce the risk of neural tube defects (NTDs) in the foetus. Folate metabolism can be altered by many factors, including adequate intake through diet. Folate deficiency can compromise the synthesis, repair and methylation of DNA, with deleterious consequences on genomic stability and gene expression. These processes are known to be altered in chronic diseases, including cancer and cardiovascular diseases.Main bodyThis review focuses on the association between folate intake and the risk of childhood leukaemia. Having compiled and analysed studies from the literature, we show the documented effects of folates on the genome and their role in cancer prevention and progression with particular emphasis on DNA methylation modifications. These changes are of crucial importance during pregnancy, as maternal diet has a profound impact on the metabolic and physiological functions of the foetus and the susceptibility to disease in later life. Folate deficiency is capable of modifying the methylation status of certain genes at birth in both animals and humans, with potential pathogenic and tumorigenic effects on the progeny. Pre-existing genetic polymorphisms can modify the metabolic network of folates and influence the risk of cancer, including childhood leukaemias. The protective effects of folic acid might be dose dependent, as excessive folic acid could have the adverse effect of nourishing certain types of tumours.ConclusionOverall, maternal folic acid supplementation before and during pregnancy seems to confer protection against the risk of childhood leukaemia in the offspring. The optimal folic acid requirements and supplementation doses need to be established, especially in conjunction with other vitamins in order to determine the most successful combinations of nutrients to maintain genomic health and wellbeing. Further research is therefore needed to uncover the role of maternal diet as a whole, as it represents a main factor capable of inducing permanent changes in the foetus.

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Can folic acid have a role in mitochondrial disorders?

Cited by 42 publications

References 45 publications

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

Identification of likely associations between cerebral folate deficiency and complex genetic‐ and metabolic pathogenesis of autism spectrum disorders by utilization of a pilot interaction modeling approach

Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature

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