title: Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia.
abstract: We reported before that the minimal alveolar concentration (MAC) of isoflurane is decreased in complex I-deficient mice lacking the NDUFS4 subunit of the respiratory chain (RC) (1.55 and 0.81% at postnatal (PN) 22-25 days 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 removed 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 by 30% (p < 0.001) in WT. In sharp contrast, it increased 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 WT and KO, respectively, whereas it tended to increase that of CIV in both WT and 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 isoflurane anesthesia interferes positively rather than negatively with the ability of CI-deficient mice brain mitochondria to convert their main substrate pyruvate into ATP.
authors: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 286 Biochemistry, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.|Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, 804 Pediatrics, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Ganesh R
authors: GR
authors: Manjeri
authors: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, 804 Pediatrics, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Richard J
authors: RJ
authors: Rodenburg
authors: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 286 Biochemistry, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Lionel
authors: L
authors: Blanchet
authors: Department of Anesthesiology, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, 549 Anesthesiology, P.O Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Suzanne
authors: S
authors: Roelofs
authors: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, 804 Pediatrics, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Leo G
authors: LG
authors: Nijtmans
authors: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, 804 Pediatrics, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Jan A
authors: JA
authors: Smeitink
authors: Department of Anesthesiology, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, 549 Anesthesiology, P.O Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Jacques J
authors: JJ
authors: Driessen
authors: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 286 Biochemistry, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands.
authors: Werner J H
authors: WJ
authors: Koopman
authors: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 286 Biochemistry, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands. Peter.Willems@radboudumc.nl.
authors: Peter H
authors: PH
authors: Willems
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000758:Anesthesia / Q000379:methods; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000378:metabolism*; D005260:Female; D007530:Isoflurane / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D007530:Isoflurane; D042967:Electron Transport Complex I