Mitochondrial roles and cytoprotection in chronic liver injury

Abstract

The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.

Figure 1

The role of hepatocyte mitochondria in liver metabolism. The liver is a central organ for the homeostasis of carbohydrates, lipids and proteins metabolism. In this context, hepatocyte mitochondria are essential in regulating the flux of metabolites in the cell in order to adjust energetic demand, ammonia detoxification, or anabolic pathways. Energy demand is met by complete oxidation of acetyl groups coming from glycolysis through tricarboxyilic acid cycle or of acyl groups coming from lipolysis through β-oxidation. Moreover, mitochondria are a unique site for metabolizing ammonia into the less toxic urea. Then, mitochondria provide shuttle proteins that allow specific addressing to anabolic pathways, as in the case of citrate transport protein (CTP) (see text for details).

Figure 2

The role of hepatocyte mitochondria in reactive oxygen species homeostasis. Mitochondria are a physiological source of reactive oxygen species (ROS). In this context, ROS exert a signaling role in cell proliferation and differentiation. However, different types of stress can target directly or indirectly hepatocyte mitochondria, such as drugs, virus, hypoxia, inflammatory cytokines, excess of β-oxidation, ectopic expression of cytochromes P450. In this case, overproduction of ROS may damage both mitochondrial and other cellular components, such as OXPHOS protein subunits, lipid membranes, mitochondrial, or nuclear DNA. These cellular lesions can favor the development of tissue lesions, such as steatohepatitis or hepatocellular carcinoma.

Figure 3

The mitochondria are central organelles in determining cell fate in liver diseases. Hepatocyte cell death is common to many liver diseases. Different stress stimuli can induce death signaling, such as toxic free fatty acids, DNA damage, endoplasmic reticulum (ER) stress observed in metabolic disease. In these contexts, mitochondria are essential to determine cell fate, as in hepatocyte the activation of the intrinsic pathway of apoptosis by cell death receptors is not usually sufficient to induce cell death and liberation of proapoptotic factors from mitochondria is a mostly necessary event. Moreover, previous alterations of mitochondrial function causing decreased ATP synthesis can induce a shift from apoptotic to necrotic cell death.

Figure 4

Mitochondria biogenesis allows tissue adaption under stress. Mitochondria biogenesis has been recently recognized as a central pathway in the adaptation of stress conditions in the liver, such as fasting, energy deprivation, hypoxia, or alcohol consumption. Different signaling pathways converge on the master regulator of mitochondria biogenesis, PGC1-alpha. In particular, AMPK and PKA signaling may activate gene transcription controlled by PGC1-alpha, while the TGF-β has been shown to inhibit PGC1-alpha-induced gene transcription.