RNA profiling and respiratory measurements of liver tissue reveals profound hepatic mitochondrial dysfunction in patients with acute-on-chronic liver failure

Background and Aims Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, organ failures and high short-term mortality. Metabolome analysis have identified inflammation-induced mitochondrial dysfunction as a hallmark of ACLF. Here, we aimed to characterize mitochondrial function and associated pathways in liver specimens of patients throughout the clinical course of cirrhosis.

Method Liver tissue was collected from patients with liver cirrhosis with (N=15) or without ACLF (N=15) which underwent liver transplantation. Bulk RNA sequencing was performed, and data processed by bioinformatic analysis. Mitochondrial respiration was measured by respirometry (Oroboros).

Results Profound changes in the liver transcriptome were observed between patients with compensated cirrhosis, decompensated cirrhosis and ACLF. In particular, ACLF was associated with distinct changes of the hepatic transcriptome. Overall, 230 genes were significantly changed in patients with decompensated cirrhosis / ACLF compared to compensated cirrhosis. Deconvolution analysis revealed significant changes in the cellular composition of the liver in ACLF regarding immune cell and hepatocyte subpopulations. Moreover, pathway analysis revealed functional enrichment in mitochondrial dysfunction, such as changes in mitochondrial translation (mitochondrial ribosomal protein family, P≤0.001). Additionally, structural changes such as mitochondrial swelling and decrease in cristae could be observed by electron microscopy. Analysis of mitochondrial respiration showed profound changes in the functionality of mitochondrial respiratory complexes in decompensated cirrhosis and in particular in ACLF.

Conclusion ACLF is associated with distinct signatures of the hepatic transcriptome. Among others, these transcriptional changes affect pathways regulating mitochondrial function, resulting in profound mitochondrial dysfunction in the liver of patients with ACLF.

Publication History

Article published online:
20 January 2025