Lee Sang Hyuk, Akpoghiran Oghenerukevwe, Cho Eunjoo, Kang So Who, Kang Min-Ji, Koh Kyunghee, Kim Eun Young
Department of Brain Science, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 16499, Republic of Korea.
bioRxiv. 2025 Aug 21:2025.08.18.670854. doi: 10.1101/2025.08.18.670854.
The circadian clock generates ~24-hour rhythms that anticipate daily environmental changes. Circadian clock and glucose metabolism are tightly interconnected, and both are disrupted in aging and disease. To examine how glucose hypometabolism impacts circadian rhythm, we downregulated glycolytic enzymes - - (-), (), and () - in clock cells. Only and knock-down (KD) altered period, lengthening and shortening rhythms, respectively. Notably, KD induced period shortening persisted in adult-specific KD (AKD), indicating a role independent of developmental effects. AKD reduced both PERIOD and Pigment-dispersing factor (PDF) protein levels, with PDF loss driving the short-period phenotype. Mechanistically, the transcriptional co-regulator TARANIS (TARA) was required: AKD lowered expression, while overexpression rescued PDF and circadian period. Our findings identify a novel PYK-TARA-PDF regulatory axis linking glycolytic activity to circadian neuropeptide output, providing mechanistic insight into how metabolic dysfunction contributes to circadian disruption in aging and neurodegenerative diseases.
昼夜节律钟产生约24小时的节律，以预测日常环境变化。昼夜节律钟与葡萄糖代谢紧密相连，且二者在衰老和疾病过程中均会受到破坏。为了研究葡萄糖代谢不足如何影响昼夜节律，我们在生物钟细胞中下调了糖酵解酶——己糖激酶（HK）、磷酸果糖激酶（PFK）和丙酮酸激酶（PYK）。只有PYK和PFK敲低（KD）改变了周期，分别使节律延长和缩短。值得注意的是，PYK KD诱导的周期缩短在成年特异性KD（AKD）中持续存在，表明其作用独立于发育效应。AKD降低了周期蛋白（PERIOD）和色素分散因子（PDF）的蛋白质水平，PDF的缺失导致了短周期表型。从机制上讲，转录共调节因子塔拉尼斯（TARA）是必需的：AKD降低了TARA的表达，而TARA过表达挽救了PDF和昼夜节律周期。我们的研究结果确定了一条新的PYK-TARA-PDF调节轴，将糖酵解活性与昼夜神经肽输出联系起来，为代谢功能障碍如何导致衰老和神经退行性疾病中的昼夜节律紊乱提供了机制性见解。
