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

Stoiljkovic, M.; Song, J. E.; Hong, H.-k.; Endle, H.; Varela, L.; Catarino, J.; Gao, X.-B.; Liu, Z.-W.; Diano, S.; Cedernaes, J.; Bass, J. T.; Horvath, T. L.

doi:10.1101/2025.03.18.643991

bioRxiv · 10.1101/2025.03.18.643991

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

Stoiljkovic, M.·Song, J. E.·Hong, H.-k.·Endle, H.·Varela, L.·Catarino, J.·Gao, X.-B.·Liu, Z.-W.·Diano, S.·Cedernaes, J.·Bass, J. T.·Horvath, T. L.

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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 cycle. Here, we show that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide (VIP)-expressing neurons show circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons cause disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons leading to desynchronization of entrainment to the light/dark cycle in Mfn2 deficient mice that resulted in 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.

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Stoiljkovic, M., Song, J. E., Hong, H.-k., Endle, H., Varela, L., Catarino, J., Gao, X.-B., Liu, Z.-W., Diano, S., Cedernaes, J., Bass, J. T., Horvath, T. L.. 2025-03-18. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms including sleep. https://doi.org/10.1101/2025.03.18.643991

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