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Two elegant studies by Moreau et al. and Zhang et al., published in the Journal of Hepatology, have revealed that AD and in particular ACLF are associated with mitochondrial dysfunction in organs and immune cells.
In detail, an untargeted serum metabolome analysis by Moreau et al. revealed a metabolite fingerprint of ACLF indicating a rise in the blood levels of fatty acylcarnitines due to depressed mitochondrial ß-oxidation in peripheral organs, which seems to be paralleled by increased extra-mitochondrial glucose and amino acid metabolism.
Zhang et al. performed an in-depth analysis of mitochondrial metabolism and ultrastructure in peripheral blood mononuclear cells (PBMCs) of patients with AD or ACLF, which identified cristae rarefication and mitochondrial swelling, as well as an impaired tricarboxylic acid cycle associated with alternative energy production from carbon and nitrogen sources.
However, these studies left open whether the described changes are accompanied by a reduction in mitochondrial respiration itself. We therefore analyzed in detail the function of mitochondrial respiration complexes in PBMCs of patients with AD or ACLF. Detailed methods are described in the supplementary methods.
Patient characteristics are shown in Table S1. One can note a typical clinical profile of patients with AD or ACLF, with the exception of high albumin levels in patients with ACLF. This is explained by the fact that some patients with ACLF had received albumin supplementation during hospitalization before progression to ACLF. Baseline respiration was slightly decreased in PBMCs of patients with AD compared to healthy controls, and significantly decreased in PBMCs of patients with ACLF (Fig. 1A). By administration of exogenous ADP complex I, respiration in these patients could be largely restored (Fig. 1B). Uncoupled respiration was not different in PBMCs of patients with AD or ACLF, compared to healthy controls (Fig. 1C). Complex II respiration, measured after stimulation of complex II by the administration of succinate and after inhibition of complex I by rotenone, was neither affected in PBMCs of patients with AD or ACLF, compared to healthy controls (Fig. 1D, E). In contrast, a profound reduction of the residual respiration in PBMCs of patients with ACLF was observed after inhibition of complex III with antimycin A, whereas PBMCs of patients with AD had similar levels of residual respiration like healthy controls (Fig. 1F). Furthermore, complex IV respiration could be only partially rescued by stimulation with ascorbate and N,N,N′,N′-tetra-methyl-p-phenylene diamine (TMPD), indicating significant impairment of complex IV in ACLF (Fig. 1G). Quantification of ATP in PBMCs revealed that the ATP content in PBMCs of patients with AD and ACLF is significantly decreased compared to PBMCs of healthy controls, indicating impaired energy supply and/or high energy consumption in the PBMCs of these patients (Fig. 1H).
Collectively, baseline, residual and complex IV respiration are reduced in PBMCs of patients with ACLF, whereas complex I, uncoupled and complex II respiration are just slightly reduced in PBMCs of patients with AD and ACLF compared to healthy controls. Remarkably, impaired complex IV respiration discriminates ACLF from AD, while deterioration of other respiration complexes shows rather a continuum with progressive disease severity. Since a high proportion of patients with ACLF had alcohol-related cirrhosis, we compared residual and complex IV respiration in patients with vs. without alcohol-related cirrhosis. No significant differences between both patient groups were observed, suggesting that our findings are specific for ACLF and not for alcohol-related liver disease (residual respiration in alcohol-related vs. other cirrhosis: 2.45 +/- 2.37 vs. 4.20 +/- 2.59; p = 0.2; complex IV respiration in alcohol-related vs. other cirrhosis: 58.75 +/- 26.59 vs. 68.15 +/- 33.74; p = 0.9). In line with this notion, Fig. 1I-J show that residual and complex IV respiration correlate inversely with the CLIF organ failure score, but not with the model for end-stage liver disease score and albumin, and that mitochondrial respiration in ACLF is clearly distinct from AD. In this regard, a specific role for mitochondrial complex IV dysfunction was linked to immunosuppression and fate of effector T cells,
Overall, our findings underline and extend those of Zhang et al., who described that there is not a general “shutdown” of mitochondrial function in PBMCs from patients with ACLF. However, in line with the findings of Moreau et al. and Zhang et al., our finding of decreased ATP content in PBMCs from patients with AD or ACLF shows that immune cells from patients with AD and ACLF suffer from reduced energy production and underlines that inflammation is energetically expensive.
This study was supported by the Deutsche Forschungsgemeinschaft (INST 20876/390-1 to CML).
MML, CE, PK, CML: study design, sample collection, data acquisition, statistical analysis, interpretation of data, manuscript writing.
Conflicts of interest
The authors have no conflicts of interest to disclose.
Please refer to the accompanying ICMJE disclosure forms for further details.
The following are the supplementary data to this article: