Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia

We reported before that the minimal alveolar concentration (MAC) of isoflurane is decreased in complex I-deficient mice lacking the NDUFS4 subunit of the respira- torychain(RC)(1.55and0.81%atpostnatal(PN)22-25days and 1.68 and 0.65 % at PN 31-34 days for wildtype (WT) and CI-deficient KO, respectively). A more severe respiratory depression was caused by 1.0 MAC isoflurane in KO mice (respiratory rate values of 86 and 45 at PN 22-25 days and 69 and 29 at PN 31-34 days for anesthetized WT and KO, respectively). Here, we address the idea that isoflurane anesthesia causes a much larger decrease in brain mitochondrial ATP production in KO mice thus explaining their increased sensitivity to this anesthetic. Brains from WT and KO mice of the above study were re- moved immediately after MAC determination at PN 31- 34 days and a mitochondria-enriched fraction was prepared. Aliquots were used for measurement of maximal ATP production in the presence of pyruvate, malate, ADP and creatine and, after freeze-thawing, the maximal activity of the individual RC complexes in the presence of complex- specific substrates. CI activity was dramatically decreased in KO, whereas ATP production was decreased by only 26 % (p<0.05). The activities of CII, CIII, and CIV were the same for WT and KO. Isoflurane anesthesia decreased the activity of CI by30% (p<0.001) in WT. In sharp contrast, itincreased the activity of CII by 37 % (p<0.001) and 50 % (p<0.001) and that of CIII by 37 % (p<0.001) and 40 % (p<0.001) in WTand KO, respectively, whereas it tended to increase that of CIVin both WTand KO. Isoflurane anesthesia increased ATP production by 52 and 69 % in WT (p<0.05) and KO (p<0.01), respectively. Together these findings indicate that isofluraneanesthesiainterferespositivelyratherthannegative- ly with the ability of CI-deficient mice brain mitochondria to convert their main substrate pyruvate into ATP.