Abstract
BackgroundMitochondrial 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. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation.MethodsWe generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways.ResultsBoth male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that 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. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria.ConclusionsThe ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.
Highlights
Mitochondrial folate enzyme Aldehyde dehydrogenase 1 family member L2 (ALDH1L2) converts 10formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH
The ALDH1L2 function is important for coenzyme A (CoA)-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis
We recently reported that ALDH1L2 maintains mitochondrial integrity in skin fibroblasts and the loss of the enzyme leads to a neuro-cutaneous disease [5]
Summary
Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10formyltetrahydrofolate 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. ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (tetrahydrofolate) to THF and CO2 in a NADP+-dependent reaction [2]. We have recently reported that the loss of the ALDH1L2 activity through deleterious mutations in the ALDH1L2 gene is linked to neuro-ichthyotic syndrome [5]. Such syndromes represent a group of rare genetic diseases commonly associated with impaired lipid metabolism [6]. This study demonstrated that ALDH1L2 is important for the mitochondrial integrity and for maintenance of the energy balance in the cell
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