1. Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure
- Author
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David Toapanta, Vicente Arroyo, Ingrid W. Zhang, Mireia Casulleras, Cristina López-Vicario, Joan Clària, María Hernández-Tejero, Javier Fernández, Ana M. Aransay, Ferran Aguilar, Benoit Colsch, Juan José Lozano, Anna Curto, Roger Flores-Costa, and Marta Duran-Güell
- Subjects
medicine.medical_specialty ,Mitochondrial Diseases ,Cirrosi hepàtica ,Cirrhosis ,Inflammation ,Mitochondrion ,Mitocondris ,Liver disease ,Tandem Mass Spectrometry ,Internal medicine ,Leukocytes ,medicine ,Humans ,Immunologic Factors ,Leucocytes ,Glutaminolysis ,Leucòcits ,Hepatology ,business.industry ,Acute-On-Chronic Liver Failure ,medicine.disease ,Inflamació ,Mitochondria ,Citric acid cycle ,Isocitrate dehydrogenase ,Endocrinology ,Hepatic cirrhosis ,Leukocytes, Mononuclear ,GDF15 ,medicine.symptom ,business - Abstract
Background & Aims Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF. Methods The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array. Results Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function analysis uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. Conclusions Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF. Lay summary Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease.
- Published
- 2022