Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2009 Dec 17;4(12):e8329. doi: 10.1371/journal.pone.0008329.
In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.
在人类中，电子转移黄素蛋白（ETF）或电子转移黄素蛋白脱氢酶（ETFDH）的突变导致 MADD/戊二酸血症 II 型，这是一种常染色体隐性遗传疾病，其特征是广泛的毁灭性神经、系统和代谢症状。我们表明，ETFDH 突变的斑马鱼突变体 xavier 和 MADD 患者的成纤维细胞表现出类似的线粒体和代谢异常，包括氧化磷酸化减少、有氧糖酵解增加和 PPARG-ERK 途径上调。这种代谢功能障碍与 xav 中的异常神经增殖有关，此外还有其他神经表型和瘫痪。引人注目的是，PPARG 拮抗剂减轻了 xav 中的异常神经增殖和瘫痪，而 PPARG 激动剂增加了野生型胚胎中的神经增殖。这些结果表明，线粒体功能障碍导致有氧糖酵解增加，通过 PPARG-ERK 途径影响神经发生，这是治疗干预的潜在靶点。
