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Background and Aims: Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg 2+ ) deficiency, which can influence liver disease progression. The mechanisms underlying Mg 2+ homeostasis dysregulation in ALD remain elusive. This study aimed to investigate the role of the Mg 2+ transporter Cyclin M4 (CNNM4) in ALD by analyzing its expression patterns in patients with ALD and preclinical animal models., Approach and Results: In this study, CNNM4 is upregulated in the liver of both patients with ALD and animal models. CNNM4 overexpression triggers Mg 2+ homeostasis dysregulation, linked to ALD progression. We propose a novel therapeutic approach for ALD treatment using N -acetylgalactosamine silencing RNA technology to specifically modulate Cnnm4 expression in the liver, improving mitochondrial function and alleviating endoplasmic reticulum stress. Notably, silencing Cnnm4 restores protein isoaspartyl methyltransferase (PCMT1) activity, essential for repairing ethanol-induced protein damage. Enhancing mitochondrial activity through Cnnm4-dependent mechanisms increases S -adenosylmethionine levels, crucial for PCMT1 function, highlighting the interconnected roles of mitochondrial health and protein homeostasis in ALD treatment., Conclusions: These findings shed light on the dysregulation of Mg 2+ homeostasis in ALD, providing a promising therapeutic approach targeting CNNM4. N -acetylgalactosamine si Cnnm4 therapy boosts the repair processes of ethanol-damaged proteins through the upregulation of PCMT1 activity., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage., Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation., Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models., Approach and Results: Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G 1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations., Conclusions: Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)