The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on function.

中文翻译：

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TDP-43 功能障碍导致人体细胞生物能衰竭和脂质代谢重新布线


TAR DNA 结合蛋白 43 (TDP-43) 的功能障碍与多种神经退行性疾病有关，但其毒性功能获得与功能丧失效应的具体贡献仍不清楚。本研究利用人类诱导的多能干细胞来源的运动神经元和 HeLa 细胞，研究细胞代谢和活力丧失的影响。沉默导致两种细胞类型的代谢活动和细胞生长减少，并伴有神经突变性和耗氧率降低。值得注意的是，耗竭会引起代谢转变，损害 ATP 产生，增加代谢不灵活性，并提高自由基产生，表明 TDP-43 在维持细胞生物能方面发挥着关键作用。此外，损失引发非凋亡细胞死亡，增加 ACSL4 表达，并重新编程脂质代谢以实现脂滴积累，同时矛盾地增强了对铁死亡诱导剂的抵抗力。总体而言，我们的研究结果强调了 ATP 产生、代谢活动、耗氧量和细胞存活等基本细胞特征高度依赖于功能。