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

Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. Here, we report an affected individual carrying a pathogenic MIC13 variant (c.260-2 A > G) associated with early-onset mitochondrial hepato-encephalopathy. Such mitochondrial hepatopathies are rare, multisystemic disorders with major liver involvement, difficult to diagnose, lack effective treatment, and are poorly understood, in part due to the absence of faithful disease-relevant cellular models. To investigate hepatocyte-specific consequences of the MIC13 variant, we generated iPSCs carrying this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a key component of the MICOS complex required for cristae formation, was disrupted in these cells, and the resultant iHeps exhibited the same cristae defects observed in clinical samples. Integrated multi-omics and biochemical analyses revealed extensive metabolic rewiring, including disrupted amino acid turnover, accumulation of tricarboxylic acid (TCA) and urea cycle intermediates. Additionally, profound alterations in methionine cycle and transsulfuration pathways, along with enhanced bile acid synthesis, collectively affect methylation potential, redox homeostasis, and detoxification. Lipid metabolism was also impaired, with incomplete β-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodeling, increased intracellular collagen accumulation and enhanced cell migration indicated an early fibrotic phenotype, linking metabolic rewiring to ECM homeostasis. Overall, this clinically relevant model uncovers how cristae defects drive metabolic imbalance and hepatocyte dysfunction, ultimately leading to early fibrotic changes in mitochondrial liver disease. These findings provide a strong mechanistic foundation for understanding mitochondrial liver disease and developing targeted therapeutic strategies.