On the other hand, AICAR was found to be the most promising compound with no detected negative effect and an overall positive score in most of the patient’s cells. The positive effect on mitochondrial biogenesis was also clearly visible by the MTG stain while the Dy was not affected. Immunocytochemistry also supported activation of AMPK. Remarkably AICAR has been given intravenously to humans in clinical trials for the treatment of hyperinsulinemia. Recently AICAR was also reported to be favorable in cytochrome c oxidase deficiency. Apparently there is a discrepancy between the mixed effect of resveratrol and the positive effect of AICAR since they both activate the same SIRT1, PGC1a axis pathway. The underlying mechanism for this inconsistency remains unclear and requires further thorough investigation. Nevertheless, we suggest that the positive effects of resveratrol on patients cells might be masked by some additional negative effects. Notably, resveratrol was reported to inhibit the mitochondrial FoF1 ATPsynthase and oxygen consumption while depleting ATP content. In fact, resveratrol alone is suggested to act as an anticancer compound by targeting mitochondria through the activation of pro-apoptotic pathways. It is Nutlin-3 therefore conceivable that resveratrol might exert a negative effect on some parameters on some individual patient’s cells with an a priori mitochondrial dysfunction. Apart from AICAR, oltipraz and bezafibrate disclosed a general positive effect, but to a lesser extent. Sodium phenylbutyrate increased ATP but also caused a slight increase of ROS and therefore the use of this compound in OXPHOS defects could be questionable. We detected only a partial correlation between individual responses in fibroblasts and residual enzymatic complex I activity in muscle, genotype or clinical presentation. Moreover, the clinical correlation between fibroblasts responses and patients response to treatment has only been proved in a few instances and further correlation studies are warranted. Nevertheless patient’s fibroblasts provide an accessible tissue for testing individual responses to additives and drugs. Taken together, we present an accessible and relative simple system using a small amount of patient’s fibroblasts for screening potential treatments in OXPHOS defects. This enables the screening to be performed on an individual basis while measuring a number of different parameters which are not limited to the measurement of a specific respiratory chain complex. Consequently the system has a wide applicability, and could be used for other defined and undefined OXPHOS defects. The authors are aware that this system is suitable for preliminary screening only, and that the results will have to be verified by precise investigation of additional parameters and mechanisms by other methods measuring OXPHOS by enzymatic assays and expression analysis on the protein and mRNA levels. Nonetheless these assays are more complex and require a larger number of cells making them much less applicable for screening purposes. We propose that rapid preliminary screening of potential therapeutic compounds in individual patient’s fibroblasts could direct and advance personalized medical treatment.