Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of alcohol-related liver disease (ARLD), non-alcoholic fatty liver disease (NAFLD), chronic hepatitis B and hepatocellular carcinoma and discuss candidates for mitochondrially targeted therapies. These conditions were chosen as they represent a large proportion of the burden of chronic liver disease and there remains a strong clinical need for new effective therapies.
The mitochondria
Mitochondria originate from an engulfed alpha-proteobacterium 2 billion years ago and have since become a near-universal feature of eukaryote cells. 1 Structurally they have an inner and outer membrane that encloses an intermembrane space. 1 Within the inner membrane is the mitochondrial matrix where vital metabolic processes such as the tricarboxylic acid (TCA) cycle occur. 1 The inner membrane has multiple invaginations termed cristae that contain the five complexes (I–V) of the electron transport chain (ETC). These are vital for the mitochondria’s main function of producing ATP via oxidative phosphorylation.
Metabolism of energy substrates generate NADH and FADH2, which donate electrons to the ETC. Movement of electrons through the ETC induces transfer of protons across the inner membrane into the intermembrane space to create an electrochemical gradient also referred to as mitochondrial polarisation. A by-product of this process is the production of reactive oxygen species (ROS), which during normal physiology has cell-signalling functions. The electrochemical gradient is released via ATP synthase (complex V), which is a turbine-like complex that converts the energy from proton movement into the phosphorylation of ADP to ATP. In addition to ATP production, mitochondria also have roles in calcium storage and homeostasis, energy homeostasis signalling, innate immune signalling and cell apoptosis.
Mitochondria are dynamic organelles that can fuse together and fissure apart under the control of fission proteins (Drp1) and fusion proteins (Mfn1/Mfn2/Opa1). Mitochondrial dynamics have key roles in mitochondrial physiology. Mitochondrial fission allows transport of the mitochondria to different cell locations as well as isolation of damaged mitochondria to allow trafficking for proteasomal degradation in a process termed mitophagy. Fusion allows the transfer of mitochondrial proteins and mitochondrial DNA (mtDNA) within the newly fused mitochondria and can therefore act as a repair mechanism. Mitochondria retain their own circular genome, which encodes 13 proteins, including subunits of the ETC complexes. This genome retains features of its bacterial origin, including having multiple copies within each mitochondrion.
Metabolism of energy substrates generate NADH and FADH2, which donate electrons to the ETC. Movement of electrons through the ETC induces transfer of protons across the inner membrane into the intermembrane space to create an electrochemical gradient also referred to as mitochondrial polarisation. A by-product of this process is the production of reactive oxygen species (ROS), which during normal physiology has cell-signalling functions. The electrochemical gradient is released via ATP synthase (complex V), which is a turbine-like complex that converts the energy from proton movement into the phosphorylation of ADP to ATP. In addition to ATP production, mitochondria also have roles in calcium storage and homeostasis, energy homeostasis signalling, innate immune signalling and cell apoptosis.
Mitochondria are dynamic organelles that can fuse together and fissure apart under the control of fission proteins (Drp1) and fusion proteins (Mfn1/Mfn2/Opa1). Mitochondrial dynamics have key roles in mitochondrial physiology. Mitochondrial fission allows transport of the mitochondria to different cell locations as well as isolation of damaged mitochondria to allow trafficking for proteasomal degradation in a process termed mitophagy. Fusion allows the transfer of mitochondrial proteins and mitochondrial DNA (mtDNA) within the newly fused mitochondria and can therefore act as a repair mechanism.Mitochondria retain their own circular genome, which encodes 13 proteins, including subunits of the ETC complexes. 1 This genome retains features of its bacterial origin, including having multiple copies within each mitochondrion.
