Stoiljkovic Milan, Song Jae Eun, Hong Hee-Kyung, Endle Heiko, Varela Luis, Catarino Jonatas, Gao Xiao-Bing, Liu Zong-Wu, Sotonyi Peter, Diano Sabrina, Cedernaes Jonathan, Bass Joseph T, Horvath Tamas L
Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Pharmacology, University of Nis School of Medicine, Nis, Serbia.
J Clin Invest. 2025 Jul 1;135(13). doi: 10.1172/JCI185000.
Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
维持细胞适应性与环境线索之间强烈的节律性相互作用,被认为是使生物体的生理和行为与日常光/暗(LD)周期的适当阶段保持一致的关键。在此,我们证明,视交叉上核(SCN)中表达血管活性肠肽(VIP)的神经元的线粒体和突触输入组织呈现昼夜节律性。通过条件性敲除VIP神经元中促融合蛋白线粒体融合蛋白2(Mfn2)所导致的线粒体动力学紊乱,引起了SCN中VIP神经元线粒体和突触的昼夜节律振荡破坏,导致Mfn2缺陷小鼠对LD周期的同步化失调,从而使其运动活动开始的相位提前、核心体温改变以及睡眠-觉醒量和结构发生变化。我们的数据提供了直接证据,表明昼夜节律性SCN时钟机制依赖于VIP神经元中由Mfn2调节的高性能线粒体动力学,以维持哺乳动物生物体日常生物节律的连贯性。