Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Nat Metab. 2023 Sep;5(9):1595-1614. doi: 10.1038/s42255-023-00873-0. Epub 2023 Aug 31.
In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
在大多数真核细胞中，脂肪酸合成（FAS）发生在细胞质和线粒体中。然而，线粒体 FAS（mtFAS）对细胞脂组的相对贡献尚未明确界定。在这里，我们表明，果蝇线粒体烯酰辅酶 A 还原酶（Mecr）的功能丧失，该酶是 mtFAS 最后一步所必需的，会导致致死，而神经元中 Mecr 的缺失会导致进行性神经退行性变。我们观察到铁硫簇生物发生缺陷和缺乏 mecr 的果蝇中铁水平升高，导致神经酰胺水平升高。降低铁或神经酰胺的水平均可抑制神经退行性表型，表明神经酰胺和铁代谢之间存在相互作用。人类 MECR 中的突变导致儿童期发病的神经退行性变，我们表明，人源性成纤维细胞显示出类似的神经酰胺水平升高和铁稳态受损。总之，本研究确定了 mecr/MECR 在神经酰胺和铁代谢中的作用，为 mtFAS 和神经退行性变之间提供了一种机制联系。
