MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease

Comprehensive multiomics datasets revealed extensive metabolic rewiring, including disrupted amino acid turnover, accumulation of TCA and urea-cycle intermediates, and profound alterations in one-carbon metabolism affecting methylation potential, redox homeostasis, and detoxification capacity. Lipid metabolism was also impaired, with incomplete beta-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodelling and enhanced cell migration indicated early fibrotic phenotype.

Overall, this clinically relevant model uncovers how cristae defects drive metabolic imbalance and liver dysfunction, leading to early fibrotic changes in mitochondrial liver disease. These findings provide the first mechanistic link between MIC13-dependent cristae disruption and hepatic metabolic failure and offer a foundation for identifying therapeutic strategies for mitochondrial hepatopathies.