A new study has determined that a single Z alpha-1 antitrypsin (ZAAT) allele can lead to impaired metabolic and mitochondrial hepatocyte function in alpha-1-antitrypsin deficiency (AATD).

The study, published in Cell Reports, employed syngeneic induced pluripotent stem cells (iSPCs) to model heterozygosity in the SERPINA1 gene.

“Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps),” the authors wrote. “We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations.”

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To test the hypothesis that a single Z point mutation in the normal MM SERPINA1 gene is sufficient to induce injury to hepatic cells, the research team used multi-omics profiling and cell engineering to correct one of the Z mutations in iPSCs from patients who were homozygous for the Z mutation.

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They then used the engineered cells to test AAT processing and protein folding compared with matched homozygous (ZZ) and MM hepatocytes. The results demonstrated that a single Z allele disrupted intracellular AAT processing and led to morphological and functional deterioration of both ER and mitochondria in a similar manner as occurs with ZZ mutations.

The authors also identified global transcriptome and metabolome alterations associated with mitochondrial dysfunction and ER stress in the homozygous and heterozygous hepatocytes. They recommend further studies to determine the underlying mechanisms by which metabolic dysregulation develops in these cells and also to assess the possibility of interrogating patient iPSCs to quantify the risk of AATD in patients who are homozygous or heterozygous for the Z mutation in the SERPINA1 gene.


Kaserman J, Werder R, Wang F, et al. Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity. Cell Rep. Published online December 6, 2022. doi:10.1016/j.celrep.2022.111775