Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals

Hepatology. 2022 Mar;75(3):550-566. doi: 10.1002/hep.32149. Epub 2021 Dec 15.


Background and aims: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models.

Approach and results: Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations.

Conclusions: Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Disease Models, Animal
  • Energy Metabolism / physiology
  • Fatty Liver / metabolism*
  • Gene Silencing / physiology
  • Graft Rejection / prevention & control
  • Liver / metabolism
  • Liver Regeneration / physiology*
  • Liver Transplantation / methods
  • Macrophage Activation / physiology*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondrial Proteins* / genetics
  • Mitochondrial Proteins* / metabolism
  • Molecular Chaperones* / genetics
  • Molecular Chaperones* / metabolism
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / prevention & control


  • Mcj protein, mouse
  • Mitochondrial Proteins
  • Molecular Chaperones