Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders

Abstract

The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.

Keywords: energy; hepatocytes; liver disorders; metabolism; mitochondrial dysfunction.

Figure 1

Mitochondrial dysfunction and disease pathogenesis. Impaired bioenergetics and increased superoxide leakage stemming from a faulty electron transport chain can initiate and promote the progression of multiple liver disorders. ATP, adenosine triphosphate; ROS, reactive oxygen species.

Figure 2

Nitro-oxidative stress production and detoxification. Within the mitochondrion, superoxide from electron transport chain activity can be readily converted to peroxide or react with nitric oxide to form peroxynitrite. To limit peroxide diffusion and synthesis of the hydroxyl radical, organisms maintain a pool of mitochondrial glutathione, whose renewal is orchestrated by glutathione reductase with the help of various NADPH-generating enzymes. ETC, electron transport chain; G6PDH, glucose-6-phosphate dehydrogenase; GPX, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; ICDH, NADP-dependent isocitrate dehydrogenase; ME, malic enzyme; MnSOD, manganese superoxide dismutase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NOS, nitric oxide synthase.

Figure 3

Defective mitochondrial processes underlying liver disorders. An increase in ROS resulting from the electron transport chain defects or environmental factors can have detrimental effects on ATP production and β-oxidation, biomolecular events that trigger the development of liver diseases. ALD, alcoholic liver disease; ATP, adenosine triphosphate; BBOX, gamma-butyrobetaine dioxygenase; CPT, carnitine palmitoyltransferase I; ETC, electron transport chain; GSH, reduced glutathione; GSSG, oxidized glutathione; KG, alpha-ketoglutarate; NAFLD, non-alcoholic fatty liver disease; ROS, reactive oxygen species.

Figure 4

HIF-1 α stabilization is facilitated by elevated succinate levels. An increase in mitochondrial nitro-oxidative stress impedes alpha-ketoglutarate dehydrogenase functionality, which leads to the pooling of alpha-ketoglutarate. The latter scavenges peroxide with the subsequent formation of succinate, an inhibitor of HIF prolyl hydroxylases. This stabilizes HIF-1α, protecting it from proteasomal degradation and allowing it to promote hypoxic conditions in the nucleus. HIF-1α, hypoxia-inducible factor; KG, alpha-ketoglutarate; NAFLD, non-alcoholic fatty liver disease; PHD, prolyl hydroxylase; ROS, reactive oxygen species.

Figure 5

Therapeutic cues aimed at mitochondrial restoration. Pharmaceutical compounds which increase mitochondrial biogenesis and mitochondria-targeted antioxidants geared to diminishing the nitro-oxidative burden can be applied to reverse the molecular events underlying the pathogenesis of liver disorders, renewing the function of this crucial organ. ATP, adenosine triphosphate; ETC, electron transport chain; GSH, reduced glutathione; GSSG, oxidized glutathione; ROS, reactive oxygen species.