Z-AAT impairs organelle homeostasis and reduces adaptive response to lipids in alpha-1 antitrypsin deficiency models

Alpha-1 antitrypsin deficiency (AATD) due to the Z variant induces hepatic accumulation of misfolded AAT polymers and liver disease. The consequences of Z-AAT accumulation on lipid metabolism, mitochondrial function, and organelle homeostasis are not yet fully understood. Investigations were conducted in Z-HepG2 cells and 3D patient-derived ZZ hepatic organoids using protein aggregation, lipid storage, mitochondrial structure and function, peroxisomal dynamics, and broad transcriptomic and proteomic studies.

Z-AAT expression resulted in intracellular polymer accumulation and decreased secretion, coupled with lipid accumulation, mitochondrial structural disruptions, heightened mitochondrial count but diminished respiratory efficiency. Metabolic analysis showed reduced oxidative phosphorylation and partial dependence on glucose metabolism.

Peroxisomes exhibited increased mass, indicative of altered lipid processing. Multi-omics analysis unveiled extensive transcriptional and proteomic modifications involving protein synthesis, lipid metabolism, and mitochondrial function. Proteomic examination confirmed stress-induced mitochondrial dysfunction, impaired lipid handling, and activation of stress response, inflammatory, and vesicular trafficking pathways.

Significantly, lipid supplementation triggered adaptive mitochondrial transcriptional responses in control cells, while Z-HepG2 cells displayed a diminished response to lipid challenge. In summary, Z-AAT accumulation disrupts hepatic lipid processing and impairs mitochondrial and peroxisomal homeostasis, resulting in reduced metabolic flexibility that may contribute to AATD-associated liver disease.