Kumar Mukesh, Wu Yumei, Knapp Justin, Pontius Catherine L, Park Daehun, Witte Rose E, McAllister Rachel, Gupta Kallol, Rajagopalan Kartik N, De Camilli Pietro, Ryan Timothy A
Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Nat Metab. 2025 Jul 1. doi: 10.1038/s42255-025-01321-x.
Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
大脑的适当供能对于维持认知功能至关重要，但脂肪酸（FA）燃烧在这一过程中的作用一直难以捉摸。在此我们表明，急性阻断神经元特异性甘油三酯脂肪酶DDHD2（复杂遗传性痉挛性截瘫的一个遗传驱动因素）或线粒体脂质转运蛋白CPT1会导致成年雄性小鼠迅速进入蛰伏状态。这些数据表明，在体内，神经元可能通过β氧化持续使源自脂滴（LDs）的脂肪酸流动，以支持神经元生物能量学。我们表明，在解离的神经元中，电沉默或阻断DDHD2会导致神经元脂滴积累，包括在神经末梢，并且源自轴突脂滴的脂肪酸以活动依赖的方式进入线粒体，以驱动局部线粒体ATP生成。这些数据证明，神经末梢在电活动期间可以利用脂滴来提供代谢支持，并且可能在体内支持神经元功能方面发挥关键作用。
