Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure

• DOI: 10.1016/j.jhep.2021.08.009
• Publication Date: 2021-08-25T03:00:05Z
• Authors: Ingrid W. Zhang; Anna Curto; Cristina López-Vi...; Mireia Casulleras; Marta Duran-Güell; Roger Flores-Costa; Benoit Colsch; Ferran Aguilar; Ana M. Aransay; Juan José Lozano; María Hernández-T...; David Toapanta; Javier Fernández; Vicente Arroyo; Joan Clària
• Keywords: Inflammation; 0301 basic medicine; Cirrosi hepàtica; Mitochondrial Diseases; Leucòcits; 610; Acute-On-Chronic Liver Failure; Inflamació; Mitocondris; Mitochondria; 03 medical and health sciences; Hepatic cirrhosis; [CHIM.ANAL]Chemical Sciences/Analytical chemistry; Tandem Mass Spectrometry; Leukocytes; Leukocytes, Mononuclear; Humans; Immunologic Factors; Leucocytes

Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated 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 emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients acutely decompensated (AD) cirrhosis, without ACLF.The study included samples AD cirrhosis (108 128 ACLF) 41 healthy individuals. Leukocyte ultrastructure was visualized by transmission electron microscopy cytosolic fluxes were determined assessing NADH/FADH2 production various substrates. Plasma GDF15 FGF21 Luminex acylcarnitines LC-MS/MS. Gene expression analyzed RNA-sequencing PCR-based glucose metabolism profiler array.Mitochondrial advanced distinguished cristae rarefication swelling. The number mitochondria per leukocyte higher patients, accompanied reduction their size. Increased C6:0- C8:0-carnitine predicted mortality whereas strongly correlated gene set signature related to activation. Metabolic flux analyses revealed mononuclear preferential involvement extra-mitochondrial pathways, supported upregulated genes encoding enzymes glycolytic pentose phosphate pathways. In ACLF, function analysis uncovered break-points TCA at isocitrate dehydrogenase succinate level, which bridged anaplerotic reactions involving glutaminolysis nucleoside metabolism.Our findings provide evidence cellular, organelle biochemical that severe dysfunction governs immunometabolism ACLF.Patients stages disease have dismal prognosis due vital organ failures lack treatment options. this study, report functioning mitochondria, are known as powerhouse, is severely impaired probably consequence intense inflammation. Mitochondrial therefore hallmark disease.