The role of mitochondrial complexes in liver diseases
image: Mitochondrial respiratory complexes (Complexes I–V) and their assembly into respiratory supercomplexes (SCs) are fundamental to liver bioenergetics, redox homeostasis, and metabolic adaptability. Disruption of these systems contributes to major liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, drug-induced liver injury, viral hepatitis, and hepatocellular carcinoma, by impairing adenosine triphosphate synthesis, increasing oxidative stress, and altering metabolic pathways. Recent advances have clarified the structural-functional interdependence of individual complexes within SCs, revealing their dynamic remodeling in response to physiological stress and pathological injury. These insights open opportunities for clinical translation, such as targeting SC stability with pharmacological agents, nutritional strategies, or gene therapy, and employing mitochondrial transplantation in cases of severe mitochondrial failure. Precision medicine approaches, incorporating multi-omics profiling and patient-derived models, may enable individualized interventions and early detection using SC integrity as a biomarker. By linking molecular mechanisms to therapeutic strategies, this review underscores the potential of mitochondrial-targeted interventions to improve outcomes in patients with liver disease.
Credit: Hai An
Introduction
The liver is a metabolic powerhouse, constantly exposed to toxins and stressors that can induce oxidative damage and mitochondrial dysfunction. Mitochondria, the cellular energy hubs, are particularly vulnerable. Their dysfunction—characterized by reduced adenosine triphosphate (ATP) production, exacerbated oxidative stress, and increased apoptosis—is a key driver in the onset and progression of diverse liver diseases. This review delves into the critical roles of the five mitochondrial respiratory complexes (I-V) and their higher-order assemblies, known as respiratory supercomplexes (SCs). It highlights how the structural and functional integrity of these complexes is fundamental to liver bioenergetics and how their disruption underpins pathologies such as non-alcoholic fatty liver disease (NAFLD), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Understanding these mechanisms offers a roadmap for novel mitochondrial-targeted therapeutic strategies.
Functions and Biological Significance of Mitochondrial Complexes
The mitochondrial electron transport chain (ETC), composed of complexes I-V, is responsible for oxidative phosphorylation and ATP synthesis. Each complex plays a distinct but interconnected role, and their dysfunction has specific implications for liver health.
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Complex I (NADH Dehydrogenase): As the largest ETC component, Complex I is crucial for initiating electron transfer and proton pumping. Its dysfunction, common in alcoholic liver disease (ALD), NAFLD, and cirrhosis, leads to redox imbalance (altered NADH/NAD+ ratio), increased reactive oxygen species (ROS), and impaired fatty acid oxidation, thereby exacerbating hepatocyte injury and disease progression.
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Complex II (Succinate Dehydrogenase): This complex uniquely bridges the tricarboxylic acid (TCA) cycle and the ETC. In HCC, reduced expression of its subunit SDHB disrupts the ETC, promoting the Warburg effect (aerobic glycolysis) and enhancing tumor cell proliferation and metastasis.
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Complex III (Cytochrome bc₁ Complex): A major site of proton pumping and a significant source of ROS. Impaired Complex III activity reduces ATP synthesis, increases oxidative stress, and promotes apoptosis via cytochrome c release. This dysfunction is implicated in NAFLD, ischemia-reperfusion injury (IRI), and DILI.
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Complex IV (Cytochrome c Oxidase): The terminal oxidase, Complex IV, transfers electrons to oxygen. Its inhibition, as seen in fibrosis, viral hepatitis, and IRI, severely compromises oxidative phosphorylation, reduces ATP output, and worsens tissue damage. In cancer, abnormal Complex IV activity helps tumor cells adapt to hypoxia.
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Complex V (ATP Synthase): This enzyme harnesses the proton gradient to synthesize ATP. Its decreased activity in chronic hepatitis and cirrhosis leads to cellular energy deficits, weakens antioxidant defenses, and can disrupt autophagy, accelerating hepatocyte dysfunction and death.
Structural and Functional Interdependence: The Role of Respiratory Supercomplexes
A paradigm shift in mitochondrial biology is the recognition that ETC complexes do not operate in isolation but form organized respiratory supercomplexes (SCs or "respirasomes"), primarily comprising Complex I, a dimer of Complex III, and Complex IV. These SCs, stabilized by lipids like cardiolipin and assembly factors like COX7A2L (SCAF1), are not merely structural curiosities but functional necessities.
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Functional Advantages: SCs enhance the efficiency of electron transfer, minimize electron leakage (thus reducing ROS production), and stabilize individual complex subunits. Complex I, for instance, is highly unstable outside of an SC.
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Pathological Disruption: In liver diseases such as NASH and DILI, oxidative damage or depletion of cardiolipin disrupts SC assembly. This destabilization leads to a cascade of mitochondrial defects: inefficient respiration, increased ROS, and metabolic inflexibility, accelerating disease pathogenesis. The dynamic nature of SCs means they can reorganize temporarily under stress but undergo progressive disintegration under chronic injury.
From Mechanisms to Therapy: Targeting Mitochondrial Complexes
The central role of mitochondrial dysfunction opens promising therapeutic avenues aimed at restoring complex and SC integrity.
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Pharmacological and Nutritional Strategies: Agents targeting specific complexes are being explored.
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NAD+ Precursors (e.g., Nicotinamide Riboside): Aim to restore Complex I function and improve OXPHOS in NAFLD.
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Coenzyme Q10: An essential electron carrier that can support Complex I/II to III activity and reduce oxidative stress.
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Cardiolipin-Stabilizing Agents (e.g., SS-31 peptide): Protect SC architecture, reducing ROS and improving mitochondrial function in models of IRI.
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Dietary Interventions: Ketogenic diets and omega-3 fatty acids have been shown to enhance SC assembly.
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Mitochondrial Transplantation: This novel frontier involves transplanting healthy exogenous mitochondria into damaged hepatocytes. Preclinical models of acetaminophen overdose and IRI show that mitochondrial transplantation can restore ATP production, reduce oxidative stress, and improve survival by integrating into host networks and reactivating biogenesis. Translational challenges include optimizing delivery routes and ensuring donor mitochondrial quality and compatibility.
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Precision Medicine and Future Directions: Given the heterogeneity of liver diseases, a one-size-fits-all approach is inadequate. Integrating multi-omics profiling (transcriptomics, proteomics) can identify patient-specific mitochondrial dysfunction signatures. This enables stratified therapy, such as targeting SDHB mutations in HCC or using patient-derived organoids to test interventions. Future research must focus on standardizing biomarker assessment (using SC integrity as a diagnostic tool), developing liver-targeted drug delivery systems (e.g., nanoparticles), and exploring gene therapy to correct assembly factor deficiencies.
Conclusions
Mitochondrial complexes and their supramolecular organization into respiratory supercomplexes are central regulators of hepatic energy metabolism, redox balance, and cellular adaptability. Their dysfunction, through impaired ATP synthesis, excessive ROS production, and destabilized structure, is a common pathogenic thread across a spectrum of liver diseases. This mechanistic understanding reveals mitochondrial complexes and SCs not just as victims of disease but as active drivers of pathology and valuable therapeutic targets. The future of hepatology lies in leveraging this knowledge through precision medicine—combining pharmacological agents, mitochondrial transplantation, and dietary strategies within a personalized framework to restore mitochondrial health, thereby improving outcomes for patients with liver disease.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00194
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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