Increased ambient temperature mitigates pathology in the Ndufs4-/- mouse model of Leigh Syndrome

van de Wal, M. A. E.; Klein, C. J. M. I.; Adjobo-Hermans, M. J.; van de Westerlo, E.; van Karnebeek, C. D. M.; Janssen, M. M.; van der Meijden, J. C.; Homberg, J. R.; Keijer, J.; van Schothorst, E. M.; Koopman, W. J. H.

doi:10.1101/2025.10.24.684321

bioRxiv · 10.1101/2025.10.24.684321

Increased ambient temperature mitigates pathology in the Ndufs4-/- mouse model of Leigh Syndrome

van de Wal, M. A. E.·Klein, C. J. M. I.·Adjobo-Hermans, M. J.·van de Westerlo, E.·van Karnebeek, C. D. M.·Janssen, M. M.·van der Meijden, J. C.·Homberg, J. R.·Keijer, J.·van Schothorst, E. M.·Koopman, W. J. H.

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Abstract

Leigh syndrome (LS) is a devastating mitochondrial disease (MD) for which there is no treatment. Together with Leigh-like syndrome (LLS), LS constitutes part of the Leigh syndrome spectrum (LSS) disorders, which are the most frequent manifestation of a primary mitochondrial disease (MD) in children. Ndufs4-/- mice are a widely used animal model to study LS pathophysiology and interventions. These mice display an isolated mitochondrial complex I deficiency and a brain-specific pathomechanism. Similar to other mouse models of human disease, Ndufs4-/- mice are routinely housed and studied at a sub-thermoneutral ambient temperature. This means that these mice experience chronic cold-stress, which potentially aggravates disease symptoms and reduces their translational value. Here, we provide evidence that housing Ndufs4-/- mice at 26 {degrees}C instead of 20 {degrees}C increases their skin, core and brain temperature. At this higher temperature, Ndufs4-/- mice displayed lower energy expenditure and, importantly, a longer lifespan, pathology reversal in specific brain regions, as well as increased voluntary locomotor activity. We conclude that ambient temperature is a previously overlooked but highly relevant disease modifier in Ndufs4-/- mice. Given the reduced mitochondrial energy production and aberrant thermoregulation in LSS and other MD patients, our findings suggest that reducing energy requirements might be of therapeutic value and/or contribute to an improved quality of life in these patients. In a broader sense, our results advocate the use of (more) thermoneutral housing to evaluate pathomechanisms and intervention strategies in murine models of human disease. SignificanceWe conclude that ambient temperature is a previously overlooked but highly relevant disease modifier in Ndufs4-/- mice. Given the reduced mitochondrial energy production and aberrant thermoregulation in LS and other MD patients, our findings suggest that reducing energy requirements might be of therapeutic value and/or contribute to an improved quality of life in these patients. In a broader sense, our results clearly demonstrate why it is essential to use a (more) thermoneutral housing to evaluate pathomechanisms and intervention strategies in translational research with murine models of human disease.

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van de Wal, M. A. E., Klein, C. J. M. I., Adjobo-Hermans, M. J., van de Westerlo, E., van Karnebeek, C. D. M., Janssen, M. M., van der Meijden, J. C., Homberg, J. R., Keijer, J., van Schothorst, E. M., Koopman, W. J. H.. 2025-10-25. Increased ambient temperature mitigates pathology in the Ndufs4-/- mouse model of Leigh Syndrome. https://doi.org/10.1101/2025.10.24.684321

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