Unveiling the 3-D Architecture of Mitochondria in Alcohol-Related Liver Disease

Alcohol-related liver disease (ALD) encompasses a spectrum of disorders resulting from excessive alcohol consumption, leading to conditions such as alcoholic fatty liver disease, alcoholic hepatitis, and cirrhosis. ALD is a major global health burden and one of the leading causes of liver-related morbidity and mortality. A key hallmark in the pathogenesis of ALD is mitochondrial dysfunction, manifesting in morphological changes, including mitochondrial swelling, cristae disorganisation, enlargement and gigantism. These alterations are often accompanied by the formation of paracrystalline inclusions, myelinated figures, and enlarged matrix granules. Functionally, these alterations disrupt oxidative phosphorylation, increase reactive oxygen species production, and promote mitochondrial DNA damage. Collectively, these factors contribute to cellular stress and injury to hepatic parenchymal cells.

Here, we investigate mitochondrial changes associated with ALD in human precision-cut liver slices (PCLS) treated with ethanol for up to 3 days. We employ stereometric and large-volume array tomography analysis, combined with AI-assisted segmentation and analysis to investigate thousands of mitochondria in human PCLS. In so doing, we reveal structural alterations in mitochondria associated with ALD, demonstrating that ethanol exposure leads to significant mitochondrial enlargement and the formation of giant mitochondria. These findings enhance our understanding of mitochondrial alterations in ALD and underscore the importance of targeting mitochondrial dysfunction as a potential therapeutic strategy for mitigating liver injury.