Abstract
Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog’s MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros’ O2k-technology and Agilent Seahorse XF technology.
Highlights
Mitochondrial damage has beneficial effects in response to acute injuries or infections through promotion of proinflammatory responses, it might be deleterious in diseases associated with chronic inflammation such as advanced liver cirrhosis (Mansouri et al, 2018)
Therapeutic interventions aimed at restoring the deranged intermediate metabolism in immune cells might sever the links between excessive mitochondrial damage and deranged immune response and have beneficial effects in patients with acute decompensation (AD) of cirrhosis and acute-on-chronic liver failure (ACLF), a syndrome developing in patients with AD characterized by the presence of organ failure(s)
Another study in murine hepatocytes detected an increment of oxygen consumption rate (OCR) after one hour of tumor necrosis factor α (TNFα)-induced damage (Kastl et al, 2014). These findings suggest that the time of exposure to inflammatory cytokines determines if mitochondrial respiration is increased as a first effort of mitochondria to supply enough energy from oxidative phosphorylation (OXPHOS), or if it is decreased as a secondary damage of prolonged inflammation
Summary
Mitochondrial damage has beneficial effects in response to acute injuries or infections through promotion of proinflammatory responses, it might be deleterious in diseases associated with chronic inflammation such as advanced liver cirrhosis (Mansouri et al, 2018). Similar to the underestimation of the role of mitochondria in immune responses, the perception of the liver is reduced to its metabolic functions This notion should be revised, since the liver is a site of complex immunological activity, involved in the production of acute phase proteins, coagulation and complement factors, cytokines and albumin, and contains a large population of resident immune cells. We highlight the characteristics of immunometabolism that goes astray in advanced stages of liver cirrhosis, the role of dysfunctional mitochondria in development of organ failures in patients with ACLF, and propose therapeutic strategies aimed at rewiring mitochondrial intermediate metabolism
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