Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms
Milan Stoiljkovic, … , Joseph Bass, Tamas L. Horvath
Milan Stoiljkovic, … , Joseph Bass, Tamas L. Horvath
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e185000. https://doi.org/10.1172/JCI185000.
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Research Article Cell biology Metabolism Neuroscience

Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms

Abstract

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.

Authors

Milan Stoiljkovic, Jae Eun Song, Hee-kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph Bass, Tamas L. Horvath

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Figure 2

Loss of Mfn2 alters mitochondrial morphology and synaptic innervations of SCN VIP neurons.

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Loss of Mfn2 alters mitochondrial morphology and synaptic innervations o...
(A) Generation scheme for mice with Mfn-depleted SCN VIP neurons. Mfn2fl/fl mice were crossed with VIP-Cre–transgenic mice to generate VIPCre/Cre Mfn2fl/fl (Mfn2–/–) and control VIPCre/Cre (CTRL) mice. (B) Representative electron microscopic images of mitochondria in VIP neurons in the SCN of control and Mfn2–/– mice at ZT7. Scale bars: 1µm. (C) Cross-sectional area of mitochondria, (D) mitochondrial coverage, and (E) mitochondrial density of cytoplasm in SCN VIP neurons of control and Mfn2–/– mice at ZT7 and ZT19. (F) Aspect ratio and perimeter of mitochondria in SCN VIP neurons of control and Mfn2–/– mice. The green box indicates the location of the zoomed-in version of the graph on the right. (G) Circularity and (H) perimeter at ZT7 and ZT19, (I) mitochondria (Mito) and ER contact per SCN VIP neuron of control and Mfn2–/– mice at ZT7, and (J) number of synapses in VIP cells at ZT7 and ZT19. n = approximately 5 cells per mouse; n = 4–6 mice per time point. (K) Cumulative distribution of mEPSC amplitude and frequency of SCN VIP neurons in control (n = 20) and Mfn2–/– (n = 16) mice measured at ZT7. (L) Cumulative distribution of mIPSC amplitude and frequency of SCN VIP neurons in control (n = 19) and Mfn2–/– (n = 20) mice measured at ZT7. Kruskal-Wallis with Dunn’s test for C, E–H, and J; 1-way ANOVA with Tukey’s test for D; Mann Whitney test for I; Kolmogorov-Smirnov test and Mann Whitney test for K and L. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.0001. (See also Supplemental Table 1 for details on the statistical information for each graph.)