How damaged mitochondria may contribute to liver disease

Mitochondria supply cells with energy, and they also play an important role in metabolism. The Institute of Biochemistry and Molecular Biology I at Heinrich Heine University Düsseldorf (HHU) and University Hospital Düsseldorf (UKD) are researching the role of mitochondria in the development of certain diseases.

In a recent study, researchers from the Institute show how damaged mitochondria may contribute to liver disease. The researchers led by Principal Investigator Dr. Ruchika Anand have published their findings in Cell Death & Disease.

Modeling mitochondrial liver disease

Disorders attributable to damaged mitochondria are referred to as mitochondriopathies. These include severe mitochondrial liver disease; the liver can be affected in around 20% of mitochondriopathies. The research focuses on the exact processes in the cell that contribute to the development of mitochondriopathies.

They studied MIC13, a protein that helps organize the inner mitochondrial membrane and its characteristic folds, known as cristae. They investigated a disease-causing MIC13 variant associated with early-onset mitochondrial hepatoencephalopathy, a severe mitochondrial liver disorder. Cell models derived from pluripotent stem cells were used as the basis for the study.

The researchers succeeded in genetically modifying these cells to generate liver cells displaying key features of the mitochondrial disease. The development of these models expands the previously limited options for researching this mitochondriopathy.

Metabolic changes extend beyond cells

The researchers demonstrated that disruption of mitochondrial cristae was accompanied by extensive changes in cellular metabolism, including alterations in amino acid, lipid and energy metabolism. These metabolic changes were also associated with changes in the extracellular matrix, including increased collagen accumulation and altered cell migration.

The extracellular matrix provides structural support around cells and helps regulate how they communicate, move and respond to their environment. Changes in the extracellular matrix are an important feature of tissue remodeling.

The findings thus suggest that mitochondrial dysfunction may influence the extracellular environment of liver cells at an early stage of disease, rather than these changes being simply a consequence of advanced liver damage.

Together, the findings reveal a link between mitochondrial architecture, metabolism and early fibrotic remodeling, highlighting how mitochondrial defects may contribute to tissue-specific disease. The cell model used also provides a platform to investigate these mechanisms further and identify potential metabolic or molecular vulnerabilities for future therapeutic strategies.

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Sadie Harley

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Robert Egan

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