S54 Preservation of mitochondrial oxidative capacity in critically ill patients balances reduction in mitochondrial biogenesis

Abstract

Background and Aims In severe sepsis, early mitochondrial dysfunction in skeletal muscle is associated with decreased biogenesis and adverse patient outcome. We hypothesised that reduction in mitochondrial content during critical illness would be balanced by enhanced capacity to produce ATP achieved by switching from glucose to fatty acid oxidation as the preferred metabolic substrate. Methods 30 critically ill patients (70% male, age 56.4 ± 19.7 years, APACHE II score 22.4 ± 6.6) were prospectively recruited Results There were reduction in both skeletal muscle mtDNA (p = 0.04) and PGC1-α (p = 0.02) from day 1 to day 7, with fold change in PGC1α correlated with the fold change in mtDNA (r 2 = 0.65, p 0.1). Protein levels of mitochondrial respiratory complexes I-V did not change significantly from day 1 to day 7 and mtDNA fold change did not correlate with fold change in complex I-V (p > 0.1). There was a weak positive correlation between feeding (protein delivered) and fold change in complex I (r 2 = 0.20, p = 0.014) and complex III protein level (r 2 = 0.20, p = 0.016). Overall levels of mitochondrial β-oxidation pathway proteins (CPT1, MCAD, ETF, DecR1) did not change whilst peroxisomal MEFII increased significantly (p Conclusion These data suggest decreased mitochondrial biogenesis over the first week of critical illness. The increase in β-oxidation proteins combined with the lack of change in respiratory chain complex concentrations during the first week suggests that the oxidative capacity of the remaining mitochondria was enhanced with increased capacity to metabolise fatty acids. These data support our hypothesis that the decreased cellular energy utilisation accompanying decreased mitochondrial biogenesis is offset by increased capacity to produce ATP through the β-oxidation of fats.