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Abstract
Liver failure is a heterogeneous condition which may be fatal and the primary cause is frequently unknown. We investigated mitochondrial oxidative phosphorylation in patients undergoing liver transplantation. We studied 45 patients who had liver transplantation due to a variety of clinical presentations. Blue native polyacrylamide gel electrophoresis with immunodetection of respiratory chain complexes I-V, biochemical activity of respiratory chain complexes II and IV and quantification of mitochondrial DNA (mtDNA) copy number were investigated in liver tissue collected from the explanted liver during transplantation. Abnormal mitochondrial function was frequently present in this cohort: ten of 40 patients (25 %) had a defect of one or more respiratory chain enzyme complexes on blue native gels, 20 patients (44 %) had low activity of complex II and/or IV and ten (22 %) had a reduced mtDNA copy number. Combined respiratory chain deficiency and reduced numbers of mitochondria were detected in all three patients with acute liver failure. Low complex IV activity in biliary atresia and complex II defects in cirrhosis were common findings. All six patients diagnosed with liver tumours showed variable alterations in mitochondrial function, probably due to the heterogeneity of the presenting tumour. In conclusion, mitochondrial dysfunction is common in severe liver failure in non-mitochondrial conditions. Therefore, in contrast to the common practice detection of respiratory chain abnormalities in liver should not restrict the inclusion of patients for liver transplantation. Furthermore, improving mitochondrial function may be targeted as part of a complex therapy approach in different forms of liver diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9927-z) contains supplementary material, which is available to authorized users.
Highlights
Liver failure is a rare but life-threatening critical illness requiring intensive care that occurs when large parts of the liver become severely damaged resulting in severe liver dysfunction
Two of three patients showed a severe decrease and one a milder decrease in the levels of all complexes of the respiratory chain on BN PAGE (Fig. 2a and b). In support of these data we detected significantly reduced activities of complex II (p = 0.008) and complex IV (p = 0.017) in all three patients and the activity of citrate synthase and the mitochondrial DNA (mtDNA) copy number were lower than controls indicating that a low number of mitochondria are present in these patients (Fig. 2c–f)
We studied liver tissue samples in a large, representative cohort of 45 patients undergoing liver transplantation for various forms of liver disease and detected mitochondrial abnormalities in several cases
Summary
Liver failure is a rare but life-threatening critical illness requiring intensive care that occurs when large parts of the liver become severely damaged resulting in severe liver dysfunction. When liver disease occurs with extra-hepatic involvement there is more reason to suspect a mitochondrial condition (Rahman 2013), isolated hepatic failure may be related to mitochondrial dysfunction (Tables 1 and 2). Genetic forms of mtDNA depletion are associated with a predominant hepatopathy, other organs (including muscle and brain) may be involved (Fellman and Kotarsky 2011), such as in epileptic encephalopathy, liver failure and visual impairment in Alpers-Huttenlocher syndrome due to autosomal recessive POLG mutations (Naviaux and Nguyen 2004). Dysfunction of mitochondrial translation may account for severe infantile liver failure (Kemp et al 2011) caused by defects in mitochondrial translation elongation factors (GFM1, TSFM) (Balasubramaniam et al 2012; Vedrenne et al 2012). The high number of mitochondrial disease genes affecting the liver highlights the importance of mitochondria in liver cell function
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