Mitochondrial Dysfunction and Oxidative Stress in Liver Transplantation and Underlying Diseases: New Insights and Therapeutics

Abstract

Mitochondria are essential organelles for cellular energy and metabolism. Like with any organ, the liver highly depends on the function of these cellular powerhouses. Hepatotoxic insults often lead to an impairment of mitochondrial activity and an increase in oxidative stress, thereby compromising the metabolic and synthetic functions. Mitochondria play a critical role in ATP synthesis and the production or scavenging of free radicals. Mitochondria orchestrate many cellular signaling pathways involved in the regulation of cell death, metabolism, cell division, and progenitor cell differentiation. Mitochondrial dysfunction and oxidative stress are closely associated with ischemia-reperfusion injury during organ transplantation and with different liver diseases, including cholestasis, steatosis, viral hepatitis, and drug-induced liver injury. To develop novel mitochondria-targeting therapies or interventions, a better understanding of mitochondrial dysfunction and oxidative stress in hepatic pathogenesis is very much needed. Therapies targeting mitochondria impairment and oxidative imbalance in liver diseases have been extensively studied in preclinical and clinical research. In this review, we provide an overview of how oxidative stress and mitochondrial dysfunction affect liver diseases and liver transplantation. Furthermore, we summarize recent developments of antioxidant and mitochondria-targeted interventions.

Figure 1.

The main intracellular sources of ROS/RNS. Many cell organelles can produce ROS, acting as a signal-transducing molecule. Excessive ROS can induce lipid oxidation, inflammatory responses, fibrosis, or cell death in the liver. The main source of ROS is generated by ETC, NADH, and FADH² are respectively involved in the TCA cycle, and β-oxidation of fatty acids donates electron and H⁺ to mitochondrial ETC. With the process of electron transfer from complex I/complex II to complex IV, electrons leak from ETC attack O₂, leading to O₂⁻ formation. O₂⁻ has a short half-life that is rapidly divided into H₂O₂ and O₂ by SOD. NOX is also the main ROS source that transfers an electron to O₂ to produce O₂⁻ and H₂O₂. Increasing mtROS activate NOXs, which, in turn, enhances mtROS generation. This feed-forward cycle between NOXs and mitochondria maintains the cellular redox homeostasis. O₂⁻ produced by ETC can respond to NO^•, which is produced from L-arginine by NOS catalysis to generate ONOO⁻. Besides, ONOO⁻ can also be produced in mitochondria, which is mainly catalyzed by mtNOS. ETC, electron transport chain; FADH2, flavin adenine dinucleotide; mtNOS, mitochondrial NOS; ONOO⁻, peroxynitrite; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NOXs, NADPH oxidases; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; TCA, tricarboxylic acid.

Figure 2.

The role of oxidative stress and mitochondrial dysfunction in hepatic cell death, inflammation, and fibrogenesis. A, Mitochondrial function could be impaired during chronic liver injury induced by the hepatitis virus, fatty acid, alcohol, and drugs. Defected mitochondrial and subsequent oxidative stress are involved in the execution of multiple programmed cell death. Proapoptotic proteins such as AIF could translocate from mitochondrial to the cytosol via permeabilization of the mitochondrial membrane and ultimately elicit caspase-independent apoptosis. Likewise, released Cytc from mitochondrial can induce caspase-dependent apoptosis by forming apoptosome and activating caspase effectors. mtROS released from impaired mitochondrial facilitates the auto-phosphorylation of RIPK1 and thus promotes necroptosis. RIPK3 could result in a massive generation of ROS by activating mitochondrial GLUD1. MLKL could mediate fragmentation of mitochondrial through activation of PGAM5 and Drp1 and consequently execute necroptosis. Besides, overloaded Ca²⁺ triggers CYPD-mediated MPT, leading to a dramatic drop of ATP and ultimately causes MPT-driven regulated necrosis. Subsequent released DAMPs from dying cells are critical effectors in hepatic inflammation and fibrogenesis. B, mtDNA and mtROS can interact with TLRs on Kupffer cells, activating NF-κB pathways and NLRP3 inflammasomes, promoting the production of pro-inflammatory cytokines. Activated NF-κB could, in turn, suppress NLRP3 inflammasomes by the elimination of defective mitochondrial, mediated by mitophagy. Activated Kupffer cells serve as an essential ROS source, amplifying inflammation and spreading cell death. C, Mitochondrial formylated peptides conjunct with FPR1 on neutrophils, which promotes neutrophil chemotaxis. Chemokines collaborated with formylated peptides, ATP and mtDNA, lead to neutrophils recruitment. D, ROS produced by Kupffer cells, neutrophils, and injured hepatocytes could transform HSCs from quiescent to functional status and further promote the proliferation of active HSCs, consequently causing hepatic fibrosis. AIF, apoptosis-inducing factor; CYPD, cyclophilin D; Cytc, cytochrome c; DAMPs, damage-associated molecular patterns; Drp1, dynamin-related protein 1; FPR1, formyl peptide receptor 1; GLUD1, glutamate dehydrogenase 1; HSC, hepatic stellate cell; MLKL, pseudokinase mixed lineage kinase domain-like; MPT, mitochondrial permeability transition; mtDNA, mitochondrial DNA; mtROS, mitochondrial ROS; NF-κB, nuclear factor kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; PGAM5, phosphoglycerate mutase family member 5; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; ROS, reactive oxygen species; TLRs, toll-like receptors.