Objectives: To determine the significance of mitochondrial function on cognitive development in children with ASD.
Methods: The cognitive development of fifteen children with ASD diagnosed with the autism diagnostic observation schedule (ADOS) was evaluated with the Vineland adaptive behavior scale (VABS). VABS scores ranged from 50 to 79. Fresh peripheral blood mononuclear cells (PBMCs) were obtained from whole blood collected in the fasting state. Mitochondrial function was measured in the PBMCs using the Seahorse 96 XF Analyzer (Seahorse Bioscience, Inc, North Billerica, MA) to measure real-time oxygen consumption rate during the sequential addition of pharmacological inhibitors. These measurements were performed at baseline and after the addition of 3 concentrations of 2,3-Dimethoxy-1,4-naphthoquinone (DMNQ), an agent that generates both superoxide and hydrogen peroxide. Parameters of basal respiratory rate, maximal respiratory rate and reserve capacity were derived from these mitochondrial measurements. For each parameter, the baseline value and the slope of the change in value with increasing DMNQ concentrations were analyzed in relation to the VABS scores. In addition, serum glutathione measurements were obtained on all participants and correlated with mitochondrial respiratory parameters.
Results: The baseline and change in Maximal Respiratory Capacity and Reserve Capacity were related to VABS scores. A higher baseline Maximal Respiratory Capacity [F(1,8)= 16.90, p<0.005] and a greater decrease in Maximal Respiratory Capacity with increasing DMNQ doses [F(1,8)=8.03,p=0.02] was associated with a lower VABS score. Similarly, a higher baseline Reserve Capacity [F(1,8)=13.25,p<0.01] and a greater decrease in Reserve Capacity with increasing DMNQ doses [F(1,8)=6.34,p<0.05] was associated with a lower VABS score. Higher oxidized glutathione was related to a greater decrease in Maximal Respiratory Capacity (r=-.68, p<0.05) and Reserve Capacity (r=-0.70, p<0.05) when challenged with DMNQ while a higher reduced-to-oxidized glutathione ratio was related to a lower baseline Reserve Capacity (r=-0.66, p<0.05).
Conclusions: These data support the notion of the existence of a subset of ASD children with mitochondrial dysfunction and support the notion that abnormalities in mitochondrial function have clinical significance. Specifically, ASD children with lower cognitive function appear to have abnormalities in Maximal Respiratory Capacity and Reserve Capacity in PMBCs. These data are consistent with the notion that PMBCs with Maximal Respiratory Capacity and Reserve Capacity abnormalities are associated with a more oxidized microenvironment. These data confirm the significance of mitochondrial dysfunction in ASD and suggest that cognitive development of children with ASD may be linked to mitochondrial function.
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