Dataset Information

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

ABSTRACT: Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. MIC13-mediated hepato-encephalopathy is a rare mitochondrial hepatopathy with profound liver involvement, yet the mechanism by which MIC13 deficiency leads to severe hepatic dysfunction remain poorly understood. Here, we report an additional individual carrying a pathogenic MIC13 variant (c.260-2A > G) that results in severe multisystem disease involving the liver, brain, and kidney. To investigate the pathological consequences of MIC13 variant specifically in the hepatocytes, we generated an iPSC-based model by introducing this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a non-ETC protein and a key component of MICOS complex essential for cristae formation, was disrupted in these cells, and MIC13-mutant iHeps exhibited the same cristae defects observed in patient samples. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313628 | GEO | 2026/09/14

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Introduction: Lambda interferons signal through the interferon lambda receptor-1 (IFNLR1) and IL10RB heterodimer to induce interferon stimulated genes (ISGs). We previously showed that proteins derived from distinct IFNLR1 splice isoforms uniquely influence gene expression and HBV replication in stem cell-derived hepatocytes (iHeps). Here, we evaluated the mechanisms of signal transduction by full-length IFNLR1 (variant 1) and a truncated variant missing part of the cytoplasmic JAK1-interacting domain (variant 2). Methods: We evaluated HEK293T cells, wild-type (WT), and IFNLR1 knock-out (KO) iHeps with doxycycline-inducible expression FLAG-tagged IFNLR1 variants using the Duolink proximity ligation assay, ImageStream flow cytometry, western blotting of JAK-STAT proteins, susceptibility to JAK1 and TYK2 inhibitors, and gene expression profiling. Results: Each variant demonstrated IFNL-induced colocalization with IL10RB, but variant 1 was more rapidly and extensively internalized. In WT iHeps with intact endogenous IFNLR1, overexpression of either variant 1 or variant 2 enabled higher IFNL-induced JAK1, TYK2, STAT1 and STAT2 phosphorylation, yet variant 2 supported less robust ISG induction than variant 1. In iHeps with abrogated endogenous IFNLR1 expression, variant 2 supported less JAK1 and TYK2 phosphorylation and ISG induction than variant 1 yet was not deficient in supporting STAT1 and STAT2 phosphorylation. Select ISGs had differential constitutive expression in IFNL-untreated variant-expressing iHeps. In iHeps expressing variant 1, WT-iHeps were more resistant than KO-iHeps to TYK2-inhibition of antiviral ISG induction yet conversely were more susceptible to TYK2-inhibition of proinflammatory ISG induction, suggesting endogenously produced noncanonical variants influence the TYK2-dependence of IFNL signaling. Conclusions: IFNLR1 variants promote differential utilization of signaling mediators to influence IFNL-induced gene expression patterns, indicating a putative role in pathway regulation.

Project description:Induced pluripotent stem cell-derived human hepatocyte-like cells (iHeps) could provide a powerful tool for studying the mechanisms underlying human liver development and disease, testing the efficacy and safety of pharmaceuticals across different patients (i.e. personalized medicine), and enabling cell-based therapies in the clinic. However, current in vitro protocols that rely upon growth factors and extracellular matrices (ECM) alone yield iHeps with low levels of liver functions relative to adult primary human hepatocytes (PHHs). Moreover, these low hepatic functions in iHeps are difficult to maintain for prolonged times (weeks to months) in culture. Here, we engineered a micropatterned co-culture (iMPCC) platform in a multi-well format that, in contrast to conventional confluent cultures, significantly enhanced the functional maturation and longevity of iHeps in culture for 4 weeks in vitro when benchmarked against multiple donors of PHHs. In particular, iHeps were micropatterned onto collagen-coated domains of empirically optimized dimensions, surrounded by 3T3-J2 murine embryonic fibroblasts, and then sandwiched with a thin layer of ECM gel (Matrigel™). We assessed iHep maturity via global gene expression profiles, hepatic polarity, secretion of albumin and urea, basal CYP450 activities, phase-II conjugation, drug-mediated CYP450 induction, and drug-induced hepatotoxicity. Conclusion: Controlling both homotypic interactions between iHeps and heterotypic interactions with stromal fibroblasts significantly matures iHep functions and maintains them for several weeks in culture. In the future, iMPCCs could prove useful for drug screening, studying molecular mechanisms underlying iHep differentiation, modeling liver diseases, and integration into human-on-a-chip systems being designed to assess multi-organ responses to compounds. We used Affymetrix microarrays to profile the global gene expression of co-culture stabilized iHeps (iMPCCs) relative to freshly isolated and co-culture stabilized primary human hepatocytes (2 donors). To assess the transcriptomic stability of iHeps in iMPCCs, RNA was extracted following 9 and 21 days of culture for hybridization to Affymetrix microarrays. The hepatic maturation state of iHeps was assessed by comparing gene expression against microarrays containing data from two primary human hepatocyte donors, both following hepatocyte isolation (day 0) and after stabilization in the micropatterened co-culture platform (day 6 and day 42 MPCCs), as previously described.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets