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 1

Circadian rhythm of synaptic innervation and mitochondrial morphology of SCN VIP neurons in LD and DD environments.

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Circadian rhythm of synaptic innervation and mitochondrial morphology of...
(A–F) Analyses of C57BL/6J mice housed in LD conditions (ZT0: lights on; ZT12: lights off). (A) Synapse density of SCN VIP-immunolabeled neurons measured using an electron microscope at ZT1, ZT7, ZT13, ZT19 under a normal LD cycle. (B) Representative electron microscopic images of mitochondria in SCN VIP neurons at ZT7 and ZT19. Scale bar: 1 μm. (C) Cross-sectional area and (D) circularity of mitochondria in SCN VIP neurons and their cumulative probability distributions at ZT1, ZT7, ZT13, and ZT19 in LD. (E) Aspect ratio and perimeter of mitochondria in SCN VIP neurons. The average value of the aspect ratio was used to determine the long/short group, and the average value of perimeter was used to determine the big/small group. (F) Percentage of 4 different groups of mitochondria in SCN VIP neurons at ZT1, ZT7, ZT13, and ZT19 under LD conditions. Small/short group at ZT1 versus ZT19; *P = 0.0372. (G–J) Analyses of C57BL/6J mice released into DD for 48 hours. (G) Density of synapses on SCN VIP neurons measured using an electron microscope at CT1, CT7, CT13, CT19 (DD condition). (H) Cross-sectional area and (I) circularity of mitochondria in SCN VIP neurons and their cumulative probability distributions at CT1, CT7, CT13, CT19 (DD condition). (J) Percentage of 4 different groups of mitochondria in SCN VIP neurons at CT1, CT7, CT13, CT19 (DD condition). Small/short group at CT1 versus CT13; **P = 0.013; CT1 versus CT19, **P = 0.015; CT7 versus CT13, ##P = 0.0069; CT7 versus CT19, ##P = 0.0086. Big/short group CT1 versus CT7, **P = 0.0072; CT1 versus CT19, **P = 0.0082; CT7 versus CT13, ###P = 0.0002; CT7 versus CT19 ####P < 0.0001. Approximately 5 cells per mice; 4–5 mice per time point (see also Supplemental Table 1 for details on the statistical information for each graph). Kruskal-Wallis with Dunn’s test for A–D and G–I; 2-way ANOVA with Tukey’s test for F and J. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.0001.