Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cell biology Metabolism Neuroscience

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

  • Text
  • PDF
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

×

Figure 3

Loss of Mfn2 in VIP neurons alters the synchronization of SCN neuronal activity.

Options: View larger image (or click on image) Download as PowerPoint
Loss of Mfn2 in VIP neurons alters the synchronization of SCN neuronal a...
(A and C) Representative confocal images (A) of VIP neurons (red) and cFos (green) in the SCNs and (C) the number of cFos+ SCN VIP neurons in control and Mfn2–/– mice at ZT7 and ZT19. Scale bars: 100 µm; insets 10 µm. (B and D) Representative confocal images (B) of VIP (red), VPAC2 (blue), and cFos (green) expression and (D) density of cFos+ cells in the VPAC2-expressing area in the SCN of control and Mfn2–/– mice at ZT7 and ZT19. Analysis is of 3 sections per mice (n = 4–5 mice/group). Scale bars: 100 μm. (E) Number of cFos-expressing SCN VIP neurons and (F) density of cFos-expressing cells in the VPAC2-expressing area in the SCN of control and Mfn2–/– mice after exposing to light for 1 hour at ZT13 (light) or stayed in the dark (no light). Analysis is of 4 sections per mice (n = 4–5 mice/group). (G) Membrane potential of SCN VIP neurons in control (n = 20) and Mfn2–/– (n = 16) mice. (H) Ex vivo MUA recordings across the entire dorsoventral span of SCN and cross-correlation analysis between dorsal and ventral neuronal population rates in control and Mfn2–/– mice (n = 3/group). The microphotograph and diagram depict the recording site locations in the SCN (labeling: 3V, third ventricle; OX, optic chiasm; AHC, anterior hypothalamic area central part). Kruskal-Wallis with Dunn’s test for C; 1-way ANOVA with Tukey’s test for D–F; unpaired 2-tailed t-test for G and H (right panel); Mann Whitney test for H (left panel). *P < 0.05, ***P < 0.005, and ****P < 0.0001. (See also Supplemental Table 1 for details on the statistical information for each graph.)

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts