Abstract
BackgroundTherapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD.Methods and FindingsBefore launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice.ConclusionsThese results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients.
Highlights
Mitochondria play a vital role by producing most of the cellular ATP via oxidative phosphorylation (OXPHOS) [1]
These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized
It was not surprising that under our experimental growth conditions, most cells with severe complex I (CI) deficiency died upon glucose withdrawal from the culture medium
Summary
Mitochondria play a vital role by producing most of the cellular ATP via oxidative phosphorylation (OXPHOS) [1]. Harlequin (Hq) mouse is a faithful model for CI deficiency, mimicking the human disease by the variability of the severity and the progression rate of symptoms [10]. This was a strong incentive to evaluate diet effect in Hq mice under realistic conditions for a mt disease to prefigure human trials. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD
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