The outcome of boosting mitochondrial activity in alcoholic liver disease (ALD) is organ-dependent

Hepatology. 2023 Feb 9. doi: 10.1097/HEP.0000000000000303. Online ahead of print.

ABSTRACT

OBJECTIVE: Alcoholic 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 recovering mitochondrial fitness without collateral oxidative damage.

DESIGN: C57BL/6 mice (Wild-type (Wt), Mcj knockout (MCJ-KO) 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, liver, gut, and pancreas where characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition.

RESULTS: 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, i.e., 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.

CONCLUSION: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

PMID:36745935 | DOI:10.1097/HEP.0000000000000303