Deng Yaqin, Vale Goncalo, Liang Yonggang, Cui Shaojie, Xu Shimeng, McDonald Jeffrey G, Ye Jin
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mol Cell. 2025 Sep 3. doi: 10.1016/j.molcel.2025.08.023.
Although polyunsaturated phospholipids are vital for cellular functions, their overaccumulation renders cells vulnerable to ferroptosis. It remains unclear how cells exposed to excess polyunsaturated fatty acids (PUFAs) prevent their over-incorporation into phospholipids. Here, we identified a mechanism by which ubiquitin regulatory X domain-containing protein 8 (UBXD8), a fatty acid (FA)-interacting protein, prevents overaccumulation of phospholipids containing docosahexaenoate (DHA), one of the most abundant PUFAs in mammalian cells. UBXD8 binds to and activates 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which specifically incorporates DHA into phospholipids. Thus, cultured cells and mouse livers deficient in UBXD8 were resistant to ferroptosis because of reduced production of DHA-containing phospholipids. Excess unsaturated FAs, including DHA, through their interaction with UBXD8, disrupt the UBXD8/AGPAT3 complex, thereby inhibiting AGPAT3-catalyzed synthesis of DHA-containing phospholipids. This FA-sensing mechanism prevents overaccumulation of DHA-containing phospholipids in cells exposed to excess DHA, thus reducing the ferroptotic potency of DHA, a property that might contribute to the health benefits of this ω-3 PUFA.
尽管多不饱和磷脂对细胞功能至关重要，但其过度积累会使细胞易受铁死亡影响。目前尚不清楚暴露于过量多不饱和脂肪酸（PUFA）的细胞如何防止其过度掺入磷脂中。在此，我们发现了一种机制，即含泛素调节X结构域蛋白8（UBXD8），一种脂肪酸（FA）相互作用蛋白，可防止含二十二碳六烯酸（DHA）的磷脂过度积累，DHA是哺乳动物细胞中最丰富的PUFA之一。UBXD8与1-酰基甘油-3-磷酸O-酰基转移酶3（AGPAT3）结合并激活它，AGPAT3可将DHA特异性掺入磷脂中。因此，缺乏UBXD8的培养细胞和小鼠肝脏对铁死亡具有抗性，因为含DHA的磷脂生成减少。包括DHA在内的过量不饱和脂肪酸通过与UBXD8相互作用，破坏UBXD8/AGPAT3复合物，从而抑制AGPAT3催化的含DHA磷脂的合成。这种脂肪酸感应机制可防止暴露于过量DHA的细胞中含DHA磷脂的过度积累，从而降低DHA的铁死亡效力，这一特性可能有助于这种ω-3多不饱和脂肪酸对健康有益。
