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

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.