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Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder

Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient.

Findings: Using Aldh1l2 knockout (KO) mouse model, we addressed the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. Though both male and female Aldh1l2 KO mice were viable and without apparent phenotype, KO males showed accumulation of lipid vesicles in the liver, the phenomenon commonly associated with abnormal lipid metabolism. Metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation, with drastically increased plasma acylcarnitine and acylglycine conjugates being indicative of impaired β-oxidation in the liver. Mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. Accordingly, the ALDH1L2 loss leads to deregulation of lipid metabolism and decreased ATP in mitochondria.

Conclusions: ALDH1L2 plays a key role in the maintenance of CoA-dependent pathways including; β-oxidation, TCA cycle and bile acid biosynthesis. Such function explains the association of the enzyme loss with rare metabolic diseases and links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.

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Human Genomics launched with BioMed Central in July 2012, transferring from its previous publisher Henry Stewart Publications. All back content is now available in the archive.

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COVID-19 and impact on peer review

As a result of the significant disruption that is being caused by the COVID-19 pandemic we are very aware that many researchers will have difficulty in meeting the timelines associated with our peer review process during normal times.  Please do let us know if you need additional time. Our systems will continue to remind you of the original timelines but we intend to be highly flexible at this time.

Aims and scope

Human Genomics is a peer-reviewed, open access journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics.

Call for papers: Genomics of COVID-19: Molecular Mechanisms Going from Susceptibility to Severity of the Disease

Guest Editors: Giuseppe Novelli, University of Rome Tor Vergata, Italy; Juergen Reichardt,  James Cook University, Australia
The current COVID-19 pandemic has highlighted the importance of science and medicine, specifically public health, in our modern societies. Countries have taken different approaches to the pandemic. Science and medicine will play an important role in our way forward in tackling COVID-19. Specifically, genetics and genomics will be central in discovering variations in virus strains and their impact on patients’ outcome, the hosts’ ability to fend off the virus and the severity of disease in patients. Furthermore, the question of long-term immunity to COVID-19 may have a genetic and genomic basis which should be investigated. Some of these human genetics and genomics investigations will undoubtedly be suitable for publication in Human Genomics. We expressly welcome submissions of manuscripts on such subjects. 

Call for Papers: Genetically Manipulated Animal Models for Human Disease

Guest Editors: Ying Chen, Yale University, USA; Won Yeong Kang, The Jackson Laboratory, USA;  Hassane Mchaourab, Vanderbilt University, USA

In recent decades, genetically manipulated animal models have been developed and used widely in the biomedical research field. Use of animal models thus serves as an important tool to elucidate mechanisms of human disease, as well as to develop new diagnostic and therapeutic strategies for the treatment of these diseases. In this topical collection, we intend to provide up-to-date information on recent genetic animal models, and new knowledge derived from these studies on the pathophysiology, diagnosis and therapeutic drugs of human disease. We invite investigators to contribute original research and review articles that describe: (i) newly developed animal models, (ii) intervention studies using animal models, and (iii) comparisons between existing models for certain diseases.


Call for Papers: Public Health Genomics

Guest Editors: George P Patrinos, University of Patras, Greece; Hongyu Zhao, Yale University, USA

Papers are invited which address current issues in human public health genomics, such as genomic surveillance of disease, genetic risk prediction, individual genome interpretation, gene-environment interactions, genetic diversity of vector-borne disease, vaccination and vaccine-based approaches against pathogens data sharing, economic evaluation in genomic medicine, and the role of big data and artificial intelligence on the development of translational tools and services and the overall future of public health.


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Human Genomics

ISSN: 1479-7364