Du Lina, Hickey Robert W, Bayir Hülya, Watkins Simon C, Tyurin Vladimir A, Guo Fengli, Kochanek Patrick M, Jenkins Larry W, Ren Jin, Gibson Greg, Chu Charleen T, Kagan Valerian E, Clark Robert S B
Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, and Children's Hospital of Pittsburgh, Pittsburgh, PA 15260, USA.
J Biol Chem. 2009 Jan 23;284(4):2383-96. doi: 10.1074/jbc.M804396200. Epub 2008 Nov 25.
Sex-dependent differences in adaptation to famine have long been appreciated, thought to hinge on female versus male preferences for fat versus protein sources, respectively. However, whether these differences can be reduced to neurons, independent of typical nutrient depots, such as adipose tissue, skeletal muscle, and liver, was heretofore unknown. A vital adaptation to starvation is autophagy, a mechanism for recycling amino acids from organelles and proteins. Here we show that segregated neurons from males in culture are more vulnerable to starvation than neurons from females. Nutrient deprivation decreased mitochondrial respiration, increased autophagosome formation, and produced cell death more profoundly in neurons from males versus females. Starvation-induced neuronal death was attenuated by 3-methyladenine, an inhibitor of autophagy; Atg7 knockdown using small interfering RNA; or L-carnitine, essential for transport of fatty acids into mitochondria, all more effective in neurons from males versus females. Relative tolerance to nutrient deprivation in neurons from females was associated with a marked increase in triglyceride and free fatty acid content and a cytosolic phospholipase A2-dependent increase in formation of lipid droplets. Similar sex differences in sensitivity to nutrient deprivation were seen in fibroblasts. However, although inhibition of autophagy using Atg7 small interfering RNA inhibited cell death during starvation in neurons, it increased cell death in fibroblasts, implying that the role of autophagy during starvation is both sex- and tissue-dependent. Thus, during starvation, neurons from males more readily undergo autophagy and die, whereas neurons from females mobilize fatty acids, accumulate triglycerides, form lipid droplets, and survive longer.
长期以来，人们一直认识到在适应饥荒方面存在性别差异，认为这分别取决于女性和男性对脂肪和蛋白质来源的偏好。然而，此前尚不清楚这些差异是否可以归结为神经元，而与脂肪组织、骨骼肌和肝脏等典型营养储存库无关。对饥饿的一种重要适应机制是自噬，这是一种从细胞器和蛋白质中回收氨基酸的机制。在这里，我们表明，培养中的雄性分离神经元比雌性神经元更容易受到饥饿的影响。营养剥夺降低了线粒体呼吸作用，增加了自噬体的形成，并且在雄性神经元中比在雌性神经元中更显著地导致细胞死亡。饥饿诱导的神经元死亡可被自噬抑制剂3-甲基腺嘌呤、使用小干扰RNA敲低Atg7或对脂肪酸进入线粒体至关重要的L-肉碱减弱，所有这些在雄性神经元中比在雌性神经元中更有效。雌性神经元对营养剥夺的相对耐受性与甘油三酯和游离脂肪酸含量的显著增加以及胞质磷脂酶A2依赖性脂滴形成的增加有关。在成纤维细胞中也观察到了对营养剥夺敏感性的类似性别差异。然而，尽管使用Atg7小干扰RNA抑制自噬可抑制神经元饥饿期间的细胞死亡，但却增加了成纤维细胞的细胞死亡，这意味着饥饿期间自噬的作用具有性别和组织依赖性。因此，在饥饿期间，雄性神经元更容易发生自噬并死亡，而雌性神经元则动员脂肪酸、积累甘油三酯、形成脂滴并存活更长时间。
