Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism.

The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a paucity of animal models. Here, we generated homozygous (Slc25a32Y174C/Y174C and Slc25a32K235R/K235R) and compound heterozygous (Slc25a32Y174C/K235R) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out (Slc25a32-/-) mouse was also generated. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32-/- mice die in utero with NTDs. None of the Slc25a32 mutations hindered the mitochondrial uptake of folate. Instead, the mitochondrial uptake of flavin adenine dinucleotide (FAD) was specifically blocked by Slc25a32Y174C/K235R, Slc25a32K235R/K235R, and Slc25a32-/- mutations. A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid ß-oxidation and amino acid metabolism being impaired, Slc25a32-/- embryos also had a subunit of glycine cleavage system-dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulation. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32-/- embryos. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice had no glycine accumulation, but had another formate donor-dimethylglycine accumulated and formate deficiency. Meanwhile, they suffered from the absence of all folate intermediates in mitochondria. Formate supplementation increased the folate amounts, but this effect was not restricted to the Slc25a32 mutant mice only. In summary, we established novel animal models, which enabled us to understand the function of SLC25A32 better and to elucidate the role of SLC25A32 dysfunction in human disease development and progression.

[Acupuncture combined with traction therapy for lumbar disc herniation: a systematic review].

To evaluate the efficacy and safety of acupuncture combined with traction therapy for lumbar disc herniation, providing the basis for future research strategies. Randomized control trials. (RCT) of acupuncture combined with traction therapy for lumber disc herniation at home and abroad from 2000 to 2013 were searched, analysis and evaluation of literature and strength of evidence were based on the principles and methods of Evidence-based Medicine. The total effective rate and curative rate were considered as primary outcome measures; pain improvement, quality of life, relapse rate and adverse effects were considered as secondary outcome measures. Seventeen RCTs were identified, Meta-analysis showed that (1) total effective rate and curative rate: acupuncture combined with traction therapy was better than single therapy (acupuncture or traction); (2) pain improvement: acupuncture combined with traction therapy was better than traction therapy; (3) relapse rate: current evidence could not support the conclusion that acupuncture combined with traction therapy was better than traction therapy. Acupuncture combined with traction therapy for lumbar disc herniation was effective. However, the included studies were with high risk of bias, important outcome measures such as quality of life, relapse rate and adverse effects were not found in most of the studies. Current evidence has not yet been able to fully reflect acupuncture combined with traction therapy for lumbar disc herniation is better than single therapy, so more RCTs of higher quality are needed to further confirm its efficacy and safety.