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.

Impaired mitochondrial complex I function as a candidate driver in the biological stress response and a concomitant stress-induced brain metabolic reprogramming in male mice

“…In one of their computational models, they predicted that cellular ATP levels would only drop after a 90% reduction in CI activity 57 . Similar lack of change in cellular ATP level has been shown in other animal and cellular Ndufs4 models, which show no, or only marginally decreased ATP production while CI activity is severely decreased 22,[57][58][59][60] . In addition, there may be several other compensatory mechanisms to maintain cellular ATP levels upon decreased CI activity, such as increased activities of other ETC complexes, or increased TCA cycle activity 22,57 .…”

Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease

“…Generation of NAD + from NAD + precursors requires high energy phosphate compounds such as ATP and phosphoribosyl pyrophosphate (PRPP) as substrates 38 . Complex I-deficiency in Ndufs4-KO results in severe energy deprivation in the brain and liver whereas muscle and heart are largely spared 8,20,39 . The organ-selective change in energy status in Ndufs4-KO mice matches the effectiveness of raising the intracellular NAD + level in the present study.…”

Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content

“…Two general mechanisms contribute to the accumulation of protons in the intermembrane space leading to increased ΔC, namely augmented oxidation of respiratory substrates or inhibition of the ATP synthase. Increased oxidation of respiratory substrates may occur, among other mechanisms, if more metabolites enter mitochondria or the activity of respiratory chain complexes increases (27,47,48). If ATP synthase is inhibited by statins, similar to the effects of oligo, protons pumped by complexes I, III, and IV would accumulate in the intermembrane space.…”